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Navigating the FDA Approval Process

Written by Patrick Henry

Interview with Doctor Sara Zacknoen, M.D. about Navigating the FDA Approval Process for New Cancer Drugs

“Cancer can take away all of my physical abilities. It cannot touch my mind, it cannot touch my heart, and it cannot touch my soul.” – Jim Valvano

In this interview with Doctor Sara Zaknoen, M.D., we discuss a bit about Sara’s background and experience and navigating the Food & Drug Administration (FDA) approval process for new cancer drugs. Sara is a medical doctor that specializes in oncology and hematology. Sara has spent the bulk of her career looking for cures to various forms of cancer, blood diseases, and immune system diseases. Sara spent 18 years working for both large pharmaceutical companies and small biotech companies, including leadership roles at Schering-Plough and Novartis. Sara has served as the chief medical officer of two successful biotech startups. Sara is an expert on the FDA approval process for new cancer drugs, and has tons of experience in how to design and manage clinical trials for new cancer drugs. Sara is now an independent consultant working with both large and small biotech companies that are developing new drugs for various forms of cancer and blood disease.

Patrick:     Hi, this is Patrick Henry, with QuestFusion, with the Real Deal…What Matters. I’m here today with Dr. Sara Zaknoen.

Sara is a medical doctor who specializes in oncology- that’s cancer-related stuff- and hematology, which is blood-related stuff.

She’s super smart, super patient, and very hardworking. That’s what it would take to be a medical doctor.

Sara’s spent the bulk of her career looking for cures for various forms of cancers, blood disease, and immune-system diseases. Sara spent 18 years working for both large pharmaceutical companies and small biotech companies, including leadership roles at Schering-Plough and Novartis.

Sara served as the Chief Medical Officer of two successful biotech startups. Sara’s an expert on the FDA approval process for new drugs, and has tons of experience on how to design and manage clinical trials of new drugs.

She’s a strong leader and just a really cool lady. Sara’s now an independent consultant working for both large and small biotech companies that are developing new drugs for various forms of cancer and blood disease.

Welcome, Sara. I’m really glad you could do this with us.

Sara:         Thank you. Thank you for the very nice introduction. I’m very flattered.

Patrick:     Tell us a little bit, for our listeners who are primarily entrepreneurs, about yourself personally and how you got into medicine and then how you got into medical research.

Sara:         I was one of those geeky kids who, at age five, knew they wanted to do something in science. Once I said the word “doctor,” I’m sure my parents were very happy to keep reinforcing that and pushing me down that road.

                  I was also interested in science and really enjoyed it. I went to college, obviously, and was the geek who had the chemistry and biology major, with a physics minor.

What got me really interested in cancer and research was actually a course that I took in undergraduate on RNA tumor viruses.

I’m going to date myself here and say that, in college, that’s when the big news about DNA cloning broke. People remember that. There were these big worries that scientists were going to release super bugs because they were using E. coli to put cloned genes into.

I took that course and I thought, “This is just so cool.” I was thinking, “Cancer is caused by viruses” and “We’re going to cure cancer.”

That’s what got me really interested in going into cancer research. Going into medicine was what I had planned to do, because I had planned to do an academic career and clone my gene.

Patrick:     You were going to make multiple Saras.

Sara:         I would clone a gene and settle into the drudgery of writing grants through the NIH, and seeing patients and teaching.

Patrick:     The academic research type of stuff. How did that evolve into getting into the more corporate side of things?

Sara:         In medicine, you first get an expertise in something, like in internal medicine, pediatrics or surgery, and then if you want to specialize beyond that, you would then take a subspecialty. As you said, mine is hematology/oncology.

                  I did three years of internal medicine, and then you do another three years of fellowship. Then you’re supposed to go out and practice as a physician, go for more training or try to get an academic job. You can’t really get an academic job because you don’t really have a publication history. You can’t fund yourself.

I took a fellowship position at the National Cancer Institute. They had what was then called the Medical Staff Fellowship Program for folks who had already completed their fellowship but wanted to do more research.

I was in a lab of a very prominent researcher, who had cloned some very important genes in B cell malignancies, which was what I was interested in. I got there and I hated lab research.

I just did not like pipetting, doing the stuff at the bench. I was much more interested in doing clinical research, writing protocols that treated patients with experimental drugs, which we also got to do there.

I transferred out of his lab into another lab and did more clinical research. Then I took an academic position doing clinical research at the University of Cincinnati College of Medicine.

What they don’t tell you is that the grant mechanisms through the National Cancer Institute and the National Institutes of Health really don’t have a mechanism to fund clinical researchers.

All of those grants basically pay for salary and lab expenses. It’s for lab-based researchers who need to buy equipment, rent lab space, hire techs and that sort of stuff.

After about four years of trying to raise enough money by writing protocols and seeing patients, I started to look at other ways in which I could use my clinical research expertise and my oncology expertise to really do what I wanted to do, which wasn’t to see patients 24/7.

I never really wanted to be a private practice doctor. I didn’t mind taking care of patients. I loved teaching the residents and medical students and fellows who we had, but really saw that if I stayed where I was, I would end up basically seeing patients 24/7.

I had been asked to be on the board of some pharmaceutical companies, like their scientific advisory committees for certain protocols. I really liked it.

I got talking with them. One thing led to another, I did a couple of interviews, and I got an offer from Schering-Plough, which is now Merck in New Jersey. It was acquired by Merck several years ago. I accepted it and the rest is history.

Patrick:     You were in New Jersey at the time?

Sara:         I was in Cincinnati.

Patrick:     You were in Cincinnati.

Sara:         I moved to New Jersey.

Patrick:     That’s interesting. I grew up in St. Louis. It’s that mid-western town. Jersey’s definitely much more of a suburb of New York. It’s very different out there.

Sara:         Yes. I lived in Hoboken, which is sometimes called the sixth borough. It’s right across the Hudson.

Patrick:     That’s cool. I lived out in Jersey for about eight months out of college. That was my first sales job. It was fun having access to New York City.

Sara:         Yes, it was fun. I lived there almost 10 years. I really enjoyed it.

Patrick:     What brought you to California?

Sara:         I came out here to take a position. An old Schering colleague had left the company, had come out here, I think in 2005, and was working with another privately owned company here in San Diego.

                  To make a long story short, the company that they were working for was acquired by a large pharmaceutical company. They didn’t want one of the compounds that this smaller company had.

My friend and another guy who he worked with decided that they would roll out a small company based around that one asset. They got some venture money around it, called me and said, “Why don’t you come out and be my Chief Medical Officer?”

I came out, interviewed, talked to the board and looked at the compound. I came out here in the fall of 2006.

Patrick:     That’s a pretty big move, especially in that stage of your career. You’re an established person, both in academia and the National Institute of Health, working for big companies.

                  What made you take the leap to become an executive in a startup?

Sara:         My plan after I joined big pharma was to learn how to do drug development in a big company, where you really learn how to do it “right.”

                  There’s money, people and expertise, and you really learn how to do things, what’s important, what things you have to look out, what things are going to be the drivers of costs and lost time and drug development.

Then I wanted to either go to a smaller company or become a consultant. I’m not a big company person. I’m not very patient with layers of management.

I’m a person who needs to feel like I’m personally making a difference, not just reading a document and passing it on to the next vice president who’s going to read it and pass it on to the next vice president.

I’m also a bit of risk taker. I have to say it. I thought, “I have to get out of the northeast.” It was cold winters and lots of travel with big pharma. It was the rat race of living near Manhattan. If you lived in Jersey, you know what that’s like.

Patrick:     It’s intense.

Sara:         It wears your soul down after a while. I actually can remember; it was January of 2006. I had come out here with other folks from Novartis. We were going to do a due diligence on a small company that was in San Diego.

                  I got here. We were staying at the Estancia Hotel. I remember sitting there, outside, looking at this beautiful ground with a wonderful glass of California Pinot Noir, and thinking, “What am I doing in New Jersey?”

Patrick:     That was very similar to me. I always wanted to move to southern California out of college. I grew up in St. Louis, went to Georgia Tech in Atlanta, then Michigan and then New Jersey.

                  When I got off the plane from New Jersey to Orange County, I moved out initially to Newport Beach, I wanted to be like the Pope and kiss the ground.

Sara:         I had never been like that. I was little Miss “Oh, I could never live in southern California. There’s no culture.” I just sat there and thought, “What are you thinking? It’s January. It was seven below when you left and you’re sitting outside.”

Patrick:     What do you think are the most important qualities for being a medical doctor and being a researcher?

Sara:         The most important quality in being a medical doctor is you really have to like taking care of people. Medicine is not all about the science. It’s probably 15% about the science and understanding medicine, and 85% listening to people’s problems.

                  In cancer, you’re there. People are very upset. Their families are very upset. You have to be there to repeat over and over what you said, because people don’t hear. It’s just such a shocking diagnosis. They just immediately shut down. Families get very upset. Families don’t communicate correctly.

To be a good physician, you really have to enjoy taking care of people, but you have to be very smart. You have to study hard. You have to know the medicine. You need to have a very good memory, because you really need to keep a lot of it right there in your brain, not a lot of time to go. You can’t say, “Wait while I go look something up.”

You can do that after, but you have to be very confident when you’re with the patient that you know what you’re doing and you’re going to lead them down the path of a course of treatment that you and the patient agree is the best thing to do.

Patrick:     That has to be super difficult in that you could die. It is a family disease. I remember a friend of mine; our daughters did Indian Princesses together. He got some kind of neck or throat cancer.

It was just awful. There was all the stuff he went through and he eventually passed away. He had two young kids. It’s something that affects the whole family.

Sara:         It does.

Patrick:     It’s crazy. I went through the FDA website, which was quite entertaining. Anything for the Federal Government always amuses me.

                  The approval process for a new drug seemed pretty simple. There’s this 12-step process with FDA phase one, two and three. There are some steps in the middle. Can you walk us through that, just in laymen’s terms?

I’ve read something in the research for this interview that it takes 12 years, on average, from the time that you have the initial idea to when a new pharmaceutical is actually available in the market. That’s serious stuff.

Sara:         It’s serious, but it’s probably true. In fact, I think 12 years from the first idea is probably a pretty good amount of time.

                  It starts with, as you say, the idea. There’s some target on a cancer cell. I can only talk about cancer. There’s some mutation in a gene. There’s something that now has been described that, say, is the cause of lung cancer.

Then you have to do the research to figure out what would be the best way to treat that mutation or to, in some way, get something to that cell that could make it right again or kill it.

That is what we call pre-clinical or development. That’s a lot of chemistry, a lot computer-aided drug design and a lot of wet medicinal chemistry.

That can take years, because you need to get a chemical compound that you can give to a human and not harm them, that isn’t going to be metabolized. Most of the drugs that we give are actually poisons. Cancer drugs are definitely poisons. We’re there to kill the tumor cells more than they kill normal cells, but they do damage normal cells.

Patrick:     This is why chemotherapy people get so sick.

Sara:         Exactly. It’s the old-time chemo. The newer drugs now, which are directed against a particular mutation that only the cancer cell has, are a little easier to take, but they do have side effects.

                  Now the new drugs that are treating immune systems, the immuno-oncology drugs, help the body’s own immune system recognize the cancer and kill it, but they also have some fairly significant side effects.

Patrick:     When I think of immune system stuff, the only thing I know as a layman out there is about AIDS or HIV. Are there other immune diseases that are related to cancers and things like that?

Sara:         Sure. Any patients that have immune deficiencies- there are inherited immune deficiencies. There are patients who are being treated with certain drugs for diseases, like rheumatoid arthritis or Crohn’s disease, that suppress the immune system. Those people have a higher incidence of developing cancers.

                  The job of the immune system is to get rid of and destroy infectious things, but also get rid of and destroy any of our own cells that have mutated and gone wrong or gone bad. Cancer is a cell gone bad.

The immune system is set up to recognize what our normal cells look like and to get rid of things that don’t look like our normal cells.

Unfortunately, cancers are very smart. They’re not really, but just by chance mutation they have developed ways in which they suppress the immune system.

They trick the immune system into thinking that they’re normal cells like everyone else. Then the body doesn’t reject it. After the cancer grows to a certain size, it’s very hard for the body’s own immune system to get rid of it.

Some of the newer immuno-oncology drugs basically unleash the body’s own immune system to re-recognize that this cancer is a danger.

Patrick:     So they’re saying, “Wake up. Fight this, because you’re being deceived that there’s not a problem?”

Sara:         Exactly. It’s very complex to design those drugs. Then you have to go through all the animal testing. Mostly in cancer it’s done in mouse models.

                  They inject human cancers into laboratory mice and then treat them with the compounds to see if the cancer goes away.

Then you have to make sure that the drug isn’t going to be metabolized or destroyed by the body’s system before it even has a chance to work.

Once you’ve gone through all of that, then you start in the human trials. As you said, phase one, phase two and phase three.

Phase one studies are where you refer to the first in human or first in man, the first time you actually give this drug that you’ve now created and manufactured to a human being. It could be a pill. It could be an intravenous thing. Usually, it’s either a pill or an IV.

You’re looking basically to see what the toxicity is, what’s going to happen. You start with very low doses. You treat small numbers of patients at your first dose. If that’s okay, then you increase the dose a little more and you treat another group of patients, until you start to see toxicity.

Patrick:     This is really all about not even curing what it’s trying to cure. You’re just making sure it doesn’t hurt the person.

Sara:         Correct. There is very little in the way of affect against the cancer in phase one studies. Sometimes you see it when the drugs are directed against a particular mutation.

                  For instance, I think a lot of folks may be familiar with a drug called Gleevec, which is a pill that’s given for a particular form of chronic leukemia.

It was developed by Novartis Oncology. It’s been out now for probably 10 years. It’s directed against the particular mutation that everyone who has this cancer gets.

There’s a mutation that happens in the precursors of their white blood cells and their bone marrow that causes these precursors to have a growth advantage. Then they take over the bone marrow.

This drug is directed against that mutation and kills the cells, and basically is a lifesaver. It’s basically turned a leukemia that was 100% fatal, unless you had a bone marrow transplant, into something that’s now a chronic disease.

When you have that type of a drug and you treat patients in your phase one study who have that mutation, then once you get to an efficacious dose, you may actually start to see some results.

However, in general, most phase one studies are looking at toxicity. How much drug can we give? What’s too much drug? What are the side effects going to be?

Patrick:     How many people are typically involved in a phase one study for a new pharma?

Sara:         Anywhere from, I would say, 20 patients to 500 patients. Again, the lines of phase one, phase two, phase three, especially with the so-called targeted agents, begin to blur.

                  If you treat patients with your targeted agent and their cancers have the target, then you see responses, and you can often just expand your study and go to the FDA with a very large phase one study and get, at least, an initial conditional approval.

In traditional, chemotherapy kinds of stuff, you probably would have anywhere from 20 up to, maybe, 100 patients in a phase one study.

Patrick:     Then phase two, you start to look at, they call it, efficacy. Is that what it is?

Sara:         Phase two you start to look at, again, safety as well.

Patrick:     Toxicity still.

Sara:         Yes. You’re treating larger groups of patients, but you’re also starting to see whether you’re starting to have effects in any of the cancers. Are you shrinking tumors? Are you making people feel better? Are you extending their lives?

Patrick:     Do you do that side-by-side with placebo type of stuff to see if there’s a difference? How does all that stuff work?

Sara:         In some designs. Some phase two studies can have a placebo, if your design is a randomized study. The patient is randomized to receive one or the other arms.

Patrick:     How do you make the decision around how to do that? When you’re designing a study, what are the things you look at? Is it stuff that you get to decide or the FDA tells you what to do? How does that work?

Sara:         No. The decision for those sorts of designs rests with the pharmaceutical company or the biotech.

                  Generally, what you’re thinking is if you have a drug that’s going to shrink a tumor on an x-ray, make it go away, or if it’s a leukemia where you can very easily, by blood counts, track it, you don’t really need a placebo to compare to, because nothing that we know is going to shrink a tumor that isn’t active.

If you’re looking at something like a time-dependent variable, things like a concept we call progression-free survival, you give the drug to the patient and you measure the time it takes for the tumor to start re-growing.

It may shrink a little bit, but it’s not going to go away. It may be become stable in size for a certain amount of time.

When you have that kind of design, you often want to have a placebo arm to compare it to, because of the way in which the FDA views that kind of data.

The FDA basically says if you shrink a tumor or make it go away, it’s probably a result of your drug. It’s much more difficult to measure things like progression-free survival. It’s probably best to have a control.

Patrick:     Interesting. How do you learn all of this stuff?

Sara:         I’ve been doing this for almost 30 years. It’s talking to lots of smart people when you first get into the industry on how to design studies, and many unsuccessful visits with the FDA where we, as a company, have said, “We’re going to do this and this to design our drug.” You always say, “Does the agency agree?”

What the agency says is, “No. We would prefer a randomized…” In that way, they may tell you what they expect. You can do it or not do it. It’s your risk.

Basically the FDA would say to you, “It’s your risk as a company, but then when you come to bring us your packet to get your drug approved then we might not be so happy if you didn’t do things the way that we told you to.”

Patrick:     Then phase three is?

Sara:         In phase two, at least in oncology, you get some idea of where your drug might work. In phase two, you start to have tumor shrinkages in patients with, let’s say, lung cancer.

                  Then phase three, you may design your study in lung cancer. These are usually larger studies. Now you’ve gone from, maybe, 100 to 200 in a phase two study to several hundred, up to 800 to 1,000 patients.

They’re generally randomized, so there’s a placebo. There’s a placebo control. You may compare yourself to a placebo, maybe your drug versus nothing, which is difficult to do, because patients with cancer don’t want the chance that they’ll be randomized to get basically a sugar pill.

Usually what you do is you add yourself to some chemotherapy that’s already approved. Everyone gets the chemotherapy, both arms. One arm gets the chemotherapy plus your drug and the other arm gets the chemotherapy plus the placebo.

They’re getting what’s called the standard of care, what they would get anyway, but then they have the chance to be given the experimental drug as well.

Those studies take several years. It takes time to enroll 1,000 patients. If it’s a survival study- I hate to say that because for people who don’t do cancer research, it’s hard to hear that your end point is the number of people who are dying or not dying- you have to weight a certain amount of time for those events to occur. You can see how that can rapidly chew up 12 years’ worth of time.

Patrick:     Yes. Then there’s post-phase three stuff that you get involved with.

Sara:         Phase four stuff is usually things after you’ve done your new drug application, after you’ve gone to the FDA.

Let’s say the FDA is approving your drug but they say they want X, Y and Z, “We want you to do a study in patients with kidney disease or in patients with liver disease, so then we have an idea of how to dose your drug in those patients” or “We want you to do a combination of your drug with this other drug.” The FDA can ask for any number of other studies.

Patrick:     Thanks, Sara. This has been really great. I’ve learned a lot. It’s been fantastic talking to you and getting to know you a little bit better as well.

Sara:         Wonderful. Thank you.

Patrick:     This is Patrick Henry from QuestFusion with the Real Deal…What Matters.

The FDA’s Drug Review Process: Ensuring Drugs Are Safe and Effective gives a simplified summary of the steps in a drug review process which includes:

  1. Preclinical (animal) testing.  This phase also includes a lot of chemistry and lab work to develop a “compound”.
  2. An Investigational New Drug application (IND) outlines what the sponsor of a new drug proposes for human testing in clinical trials.
  3. Phase 1 studies (typically involve 20 to 80 people).  The focus is on toxicity (does the drug make you sick, and if so at what dosages).
  4. Phase 2 studies (typically involve a few dozen to about 300 people).  The focus is still on toxicity, but also on efficacy (does the drug help solve the problem).
  5. Phase 3 studies (typically involve several hundred to about 3,000 people).  This is an expanded look at toxicity and efficacy in a larger population with other parameters being considered, like combination with other drugs, and different types of patients.
  6. The pre-NDA period, just before a New Drug Application (NDA) is submitted. A common time for the FDA and drug sponsors to meet.
  7. Submission of an NDA is the formal step asking the FDA to consider a drug for marketing approval.
  8. After an NDA is received, the FDA has 60 days to decide whether to file it so it can be reviewed.
  9. If the FDA files the NDA, an FDA review team is assigned to evaluate the sponsor’s research on the drug’s safety and effectiveness.
  10. The FDA reviews information that goes on a drug’s professional labeling (information on how to use the drug).
  11. The FDA inspects the facilities where the drug will be manufactured as part of the approval process.
  12. FDA reviewers will approve the application or issue a complete response letter.

According to MedicineNet.com, it takes an average of 12 years from the invention of a new drug to market in the United States.  Navigating through the FDA approval process is not a simple task, and Doctor Sara Zacknoen is an experienced navigator.

In cancer you are dealing with life and death.  You are dealing with patients that are very upset.  You are dealing with families that are very upset.  As a medical doctor, Sara says that 85 percent of the role is dealing with people, and only 15 percent is about the science.  All I know is it must be very difficult, and Sara is really good at what she does.

I hope you find this interview as interesting and informative as I did.  Please let me know your thoughts!

Patrick Henry Entropic

This is Patrick Henry, the CEO of QuestFusion, with The Real Deal…What Matters.

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