Like many people starting out in the biotech industry, I wanted to make an impact on people’s lives by developing life-changing therapies. But I’ve become disappointed by what I believe are too many companies pushing mediocre and me-too drugs, also known as copycat drugs, into clinical development where they will likely fail.

Clinical trials are more than a way to test new therapies. They offer very sick people hope and a chance for more time with their loved ones. Lately, the drug development process has turned into an exercise in me-tooism — at patients’ expense. It’s time to shift the focus back to those who matter most.

During a recent panel discussion, Richard Pazdur, who directs the Food and Drug Administration’s Oncology Center of Excellence, called for companies to reevaluate their current clinical trial processes. He rightfully criticized the industry’s repeated attempts at testing an approach in a disease indication after it has failed multiple times.

advertisement

Pazdur used the example of checkpoint inhibitors (drugs that target PD-1 or PD-L1) for multiple myeloma. Three recent studies were conducted close together, and although they were well-controlled and well-managed with data safety review boards, multiple studies showing negative results were not needed, he said.

There is no question that replicating studies has value, but in this situation the industry was duplicating harm to patients, as all three studies showed decrements in overall survival.

This problem isn’t limited to multiple myeloma.

With six checkpoint inhibitors on the market, do patients and their doctors really need more of the same? While these drugs are transformative for some, they don’t help the majority of people who take them. What’s more, their use is usually accompanied by harsh side effects. Despite this, the Cancer Research Institute estimates that a whopping 2,250 clinical trials are currently underway for PD-1 or PD-L1 agents — 748 more trials than a little over a year ago.

Is this really the best we can do or strive for? When people enroll in cancer clinical trials, they are placing their lives in our hands. Many have advanced disease and turn to a clinical trial for hope and possible healing. Yet as an industry, we are competing for these patients to test me-too drugs with significant toxicity, sometimes based on marginal preclinical data.

Pazdur said that patients are not a company’s resource. He’s right. They are people who are hoping for a chance at recovery, or at least more time with their families with reasonable quality of life. We should treat patients who volunteer for clinical trials the way we would treat our mothers or husbands or best friends.

Pazdur asked companies to be more efficient by collaborating, sharing data, and conducting platform trials. Some biopharmaceutical companies are trying to do this, but the industry has a long way to go. We should be moving drugs into clinical development only when there’s a strong understanding of disease biology and substantial evidence that a drug has the potential to truly improve lives.

This means rethinking what is an acceptable toxicity profile for a cancer drug and no longer accepting that feeling horribly ill is par for the course for cancer treatments. The drug industry has spent more money to develop more oncology drugs in the last few years than ever before, yet we have not made significant headway in providing broadly effective cancer therapies with limited toxicity. It’s a given that effective oncology treatment will involve combinations of drugs. We need to identify those combinations that offer the appropriate risk for the benefit and allow for a reasonable quality of life.

To develop effective cancer drugs that are well-tolerated, we must slow down and invest the time and dollars at the earliest stages of cancer biology, as well as in preclinical and early-stage clinical trials, ideally leveraging key biomarkers to accurately measure a drug’s effects and identify responders, in order to evaluate if a drug is really worth pushing through late-stage studies into larger populations. Along the way, each company bringing drugs to clinical trials should always be asking: Would I give this drug to a loved one?

By raising the bar, we can give people with cancer new drugs that give them more time with their families and friends without debilitating side effects. We owe it to the millions of people diagnosed with cancer who are looking towards clinical trials as their last hope. And we should accept nothing less.

Pazdur warned that he and the FDA are not pleased with the current state of affairs in the biopharmaceutical industry. We need to take this rebuke to heart, seriously reevaluate our current processes, and once again put patients at the heart of clinical trials.

Gail McIntyre, Ph.D., is the chief scientific officer of Aravive (ARAV), a biotechnology company based in Houston.

Leave a Comment

Please enter your name.
Please enter a comment.

  • While I agree that the methodolgy for clinical trials is complex and often painfully redundant, there is a problem to this argument.

    From step one, obtaining an IND, the FDA and other regulatory authorities place unrealistic expectaions. It is not enough to find a drug that works in humans, but it also has to work in mice to prove that we can use it in humans. As every cell type has different receptors, i.e. a liver cell, a blood cell, and a nerve cell will process a drug differently, we first have to prove that mice are okay with the drug. That is a false comparison. How many good drugs have been killed because a mouse couldnt tollerate it? how many bad drugs advance because a mouse can tollerate it?

    Second is that the 3 studies you mentioned likely had different parameters. A investigational drug is seldom give alone in late phase studies, so they were likely running concurrently so it could be tested on different populations to keep the data isolated. Heck, those studies could have been measuring differences in pk/pd in administraion modalities.

    Next, for these purposes, the FDA has rigid documentation structuring so any submission has to be shaved to fit the ectd model, even if it is more complicated than the model allows for.

    Finally, while a low adverse event, highly tollerable medication is ideal, oncology drugs kill cells. At their core, they cause death, the only question is what method you choose to administer that death. Everything has a side effect. AEs are identified in placebo only trials.

    How many canver drugs do we need? How many ways can an ocogene mutate? That is how many we need.

    In the end, genetic manipulation of leukocytes and immunotherapy is probably the answer, but what few drugs are approved in this sphere cost 500,000+ per treatment because the drug is modified cells from the host, so until the patent for that process expires and it becomes afordable, other treatment avenues are needed.

    Now… Can we talk about companies expanding their patents for life saving anything by “finding a new indication” just before the patent exires; all to monopolize the market and prevent competition and generics?

  • Good article. As we know, cancer is a lucrative market and many of the me-too type drugs are made for profit and profit alone ! Once there is an approval , the next copy-cat drug attempts to piggyback off the success by claiming some improvement on the drug which in many cases is insignificant. Some cancers that are less common like sarcoma do not get the attention they deserve.

    • So Neil….sometimes I think the entire cancer industry is a hugh cash register that doesn’t really want to find cure but string people along. I know this is a cynical perspective and a passing thought as no one is forcing me (us) to buy these treatments But how can we discern an drug that is insignificant or not? Secondly any thoughts on these to procedures: Appleby and Nanoknife? I’ve mixed reviews. Are they the real deal or just another money makers? Thanks for your and anyone else input.

    • Steven, every cancer is different. That sounds cliche, but all those tests are to identify what drives your cancer, where it is, etc. Remember, cancer is in the cell, a genetic mutation within a cell, it isnt always a lump or mass. Let me be clear – cancer is profitable for drug companies, hospitals, etc., butthe notion that there is not a push for a cure is wrong, the problem is there isnt A cure. If a hematologist tests a leukemia drug and it fails, do we scrap it or test it on endocrine, bone, skin cancers? Well, depends on how it tested in mice. The problem is you are not a mouse, and your cells will not respond the same – mine and your cells may respond differently so what works on you may not work on me, etc. Drug manufacturing is trial and error, and that is scary to think about, so there is a LOT of red tape in place to minimize the chances of error, but often this the chances of success too. Lets say a regimen needs to happen on a certain cycle (often to kill cells at specific miotic phases), but your cells, for what ever reason, divide on an abnormal schedule, well now you are getting all the negatives and non of the benefits, you progress. But drugs are tested on cycles, and for your insurance to pay for it it has to be administered according to the label. Now, you get new scans and a new, second line therapy.

      Everyone is different.

  • While Gail McIntyre makes several good points, I want to speak as a patient for the other point of view.
    I am currently a more than two year survivor of stage four pancreatic cancer– a Pnet version– solid Pseudopapilary neoplasm. I did not qualify for radiation or surgery. Neither frontline chemo worked for me.
    I had a very successful and easy trial with Durvamalab( Imfinzi) and AZD9150. I had few side effects and it kept me stable for about seven to eight wonderful months before the cancer figured out a way to keep growing. My trial was a pdl1 inhibitor, I believe.
    Now I am starting a new biologic phase 1 trial. I am so grateful for how my doctor at MD Anderson cares about me and fights for me. She is the best clinical trial doc in the universe.

    I also have many friends dealing with pancreatic cancer. I hear their heartbreak when they are told “We have no trials that you qualify for. ” That hopeless tone of defeat from a doctor is one of the worst things a person can hear. When people are still wanting to try but nothing is offered, it is like being told “there is no hope for you and we are sending you home to die.” I sat with a friend whose doctor told her that. She sucked up her courage and acted bravely. but I know she would habe tried a trial if it was available. Partly because she had no hope, she went home and passed away although she was physically doing better than I was.
    It doesn’t seem right that some of us get into trials and others don’t get a chance.
    Besides, we can always say “No” if a trial really has dismal results.

    We love that “right to try” decision that came down recently.

    I am here as long as God wants me here. I have already surpassed the “three months without chemo and six months with” I was told.

    Make decisions in favor of giving patients more choices , not less, if they have no remaining standard options and continued disease progression.
    Really you do us no favors by advocating for patients to have no options presented. We can look at the trial document and make an educated decision, and we can always stop a trial. Cancer makes us very aware of the preciousness of each day. Many of us are fighting to be around to raise our children or see a daughter get married.
    Hope is sacred. Showing respect for patients by allowing them to make choices, even if not ideal, is so much more empowering for a person who still wants to live.
    Let my people hope.

    • Thank you Pam for the insight. I am S4 Pancan…made it near two years for which I am incredible grateful. I am concerned a bit but I a near trust God more now than ever, that maybe Lee Moffitt my provide is not totally focus on me. They do a great job and I love my physician and team but think they are overwhelmed and under staffed. I have inoperable adenenoma. And information you might come across please share. We are work with Pancan assoc. And looking at Sloan as a possible change or Clinial trail..any thoughs. We’re in Florida. Close for now…our prayers go out to you and your loved ones.

  • Why is there so little being done around Pancreatic cancer in terms meaningful resources being spent on intensive result oriented and successful cures measured relative to other cancers, e.g. breast, lung.
    It is astonishing to me that we as a country will spend more money on the opioid issue than Pancreatic Cancer research. This opioid problem is not the fault of Johnson & Johnson, they did not make the addicted person use these drug irresponsible just like the liquor producer don’t make one become alcoholics. We need to redirect our attention and stop politicizing issues like the opioid problem and help cure Pancreatic cancer.

    • I am currently a more than two year survivor of stage four pancreatic cancer– a Pnet version– solid Pseudopapilary neoplasm. I did not qualify for radiation or surgery. Neither frontline chemo worked for me.
      I had a very successful and easy trial with Durvamalab( Imfinzi) and AZD9150. I had few side effects and it kept me stable for about seven to eight wonderful months.
      Now I am starting a new biologic phase 1 trial at MD Anderson.
      https://www.soricimed.com/sor-c13.htm
      Maybe one of them could work for you.

    • Pancreas genes express differently than most cells, and it is compounded by the fact that the pancreas has a role in metabolism and produces enzymes. For a drug to work, we have to know what it will look like when it gets to the target. The pancreas makes this hard and a pancreatectomy is a crap shoot, and fairly new medicine. Organs can be harder to nail down. And a viable animal model has to exist before in human trials are approved.

  • There is good and bad in the current development of cancer therapies. No one will question the need for new, better, less toxic cancer treatments. If they were currently in development no company would prioritize a “me too” drug over a new better therapy. So the question is not should we develop these new treatments but is there a space for me too drugs.

    To me the answer is yes. Who would believe we would have a trial demonstrating the benefit of a check point inhibitor for Merkel cell carcinoma if not for the fact that there are 6 checkpoint inhibitors and one of them had to find a space that was not currently occupied with another agent.

    If Nivolumab was the only checkpoint inhibitor would we ever of found the benefit of combinations with chemotherapy in NSCLC or with Chemoradiotherapy in stage III disease? Likely not for a long time as there would have been much less pressure on the company to do these trials.

    Do do we need more then 6 checkpoint inhibitors? Yes, why? Most companies with new checkpoint inhibitors are developing them with new immune combination. If the combinations are positive they could bundle the treatment into a single cost giving them a competitive price advantage, versus needing to combine their new drug with the cost of a checkpoint inhibitor already on the market. This could ultimately lead to savings both for developmental cost and for the cost of treatment.

    There are a lot that needs to be done to improve the efficiency of clinical research, but i would continue to encourage both innovations and more “me too” drugs. Ultimately competition we bring cost down, as you can see from the new TRK inhibitor from Genentech.

  • “Pazdur used the example of checkpoint inhibitors (drugs that target PD-1 or PD-L1) for multiple myeloma. Three recent studies were conducted close together, and although they were well-controlled and well-managed with data safety review boards, multiple studies showing negative results were not needed, he said.”

    But these were all started around the same time, so without knowing the results (failure) of any one of them, there was no reason NOT to run them. Then once these trials start failing and it was publicized, literally no one will run another one like this with PD-1 inhibitor for MM. How can you fault running “me-too” studies for not knowing results ahead of time?

    • Dear Pam
      Yes hope is precious. There is nothing without hope. And yes. Only God knows. Clinical trials give hope and this is an invaluable gift to patients and their families. Every cancer patient is heroic. Their loved ones marvel at their strength. Keep the hope and the strength up.

      Gail McIntyre please keep these good articles coming. Noting that patient participation in Clinical trials is commendable and that they should be considered not unlike family members of pharmaceutical companies reminds us of keeping compassion part of experimentatal drugs

A roundup of STAT’s top stories of the day in science and medicine

Privacy Policy