The content on or accessible through Medpedia.com is for informational purposes only. Medpedia is not a substitute for professional advice or expert medical services from a qualified health professional.
Read more
Medpedia Answers
(Oncology/Cancer)Medpedia Answers is a platform for asking and answering questions about health and medicine. Read more.
What percentage of anti-cancer drugs that enter Phase 1 clinical trials are ultimately approved by the FDA? How many fail due to intolerable toxicities versus lack of (sufficient) efficacy?
I am interested in the difficulties of translating pre-clinical success to clinical efficacy.
asked Mar 29, 2011 at 12:47PM in Oncology/Cancer
-
Good question!Jeff Jue commented Jun 14 at 12:04AM
-
2Votes
answered Mar 30, 2011 at 08:44AMThis may be helpful until an expert on this site answers your question. I am hoping an expert will provide you with the precise statistics, as I am interested as well:
http://clinicaltrials.gov/ct2/info/results
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/default.htm
http://www.nejm.org/doi/full/10.1056/NEJM200506093522319
http://www.lymphomation.org/clinical-trial-design.htm
http://dels-old.nas.edu/ilar_n/ilarjournal/51_3/pdfs/v5103Gordon.pdf
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668727/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668727/
http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=32365
http://en.wikipedia.org/wiki/Clinical_trial -
2Votes
answered Mar 30, 2011 at 10:09PMThe recent biotechnology industry association BIO data show that the success rates of new drugs from Phase I to FDA approval is a low 9%.
Key findings from the BIO study include:
• Overall success rates from Phase I to FDA approval is nearly 9%. This number is comprised of lead and secondary indications. When separated, lead indications have close to a one in seven rate of approval and secondary indications have a rate of one in 30.
• The study also shows that large molecule drugs are twice as successful in gaining approval than small molecule drugs. New oncology drugs have the toughest time making their way through the clinic, despite cancer being the most closely studied area in drug development.
http://insidebioia.com/
New Drug Approvals FDA/EMA 2011
http://knol.google.com/k/-/-/3fy5eowy8suq3/148#-
Although I didn't ask the question, I appreciate your expert advice, Krishan. That is a very low approval rate. Do you know why (toxicities, lack of a better effect than that already used, or....?)Kim M Robinson commented Mar 31, 2011 at 09:26AM
-
Why are large molecule drugs more successful than small molecule drugs in gaining approval?Nina Evans commented Apr 03, 2011 at 05:46PM
-
-
2Votesanswered Apr 01, 2011 at 03:19AMPhase I trials of anticancer drugs are about safety or toxicity only, so if a new compound fails to go to Phase II, the failure is attributed to toxicity. Other reasons for Phase I failure are lack of drug bioavailability, absorption, distribution, excretion, failure to reach target organs like the brain, accumulation in undesired tissues/organs and unsuitable formulation. Phase II and III are about efficacy so failure can be attributed to lack of efficacy. Other causes are difficult to reach end point or lack of clear advantages over existing drugs. Each year only about 100-200 new drugs enter Phase I?
So if we take 1000 new anticancer projects in Phase I, 820 projects fail due to toxicity in Phase I. Anticancer drugs have higher chances of passing Phase I as toxicity for life saving conditions is not the main issue. Similarly biologics are better tolerated and toxicity not a major concern. Out of the 180 compounds entering Phase II, only 36 will go into Phase III. Only 18 out of 36 will pass Phase III trials. Out of 18 drug dossier filed with the FDA and EMA, only 12 may obtain approval to make it to the market. Out of 12 approved drugs, only 4 recover the R&D costs and are profitable, 4 have moderate sales and 4 are market failure. All new anticancer drugs must show survival benefits which requires longer term trials in large number of patients.-
So, in oncology the overall approval rate is more like 1.2%? In the BioMed Tracker presentation (http://insidebioia.files.wordpress.com/2011/02/bio-ceo-biomedtracker-bio-study-handout-2-15-20111.pdf) they give overall "success" rates of 11% for primary indications and 2% for secondary indications, a Phase II success rate of 29% and a Phase III success rate of 34% for oncology drugs. Can you help me make sense of these numbers together? Thank you very much for all your help!Brittany P Kay commented Apr 01, 2011 at 05:42PM
-
-
0Votesanswered Apr 02, 2011 at 10:04AMI also noticed the discrepancy in numbers that Brittany did, and as I know Krishan you work in the area of pharmaceuticals and clinical trials, I trust your numbers. That said, is there "sugarcoating" in numbers found elsewhere, or perhaps the Biomed Tracker data is for only the four leading cancers, or such, rather than including all cancers? Any data can be skewed any which way, and it is not necessarily wrong, but be include or preclude data used elsewhere.
Another thing, I am aware that the statistics you provide are likely for all oncology medications (monoclonals, TKIs, and chemotherapies), which includes the "biggies" like breast cancer. I am wondering if drug research and ultimate approval is statistically worse for the "small" cancers, whereby the ultimate profit is not worth the R&D investment because of numbers of users?
I am thinking of Chronic Lymphocytic Leukemia, for example, which is the most prevalent adult leukemia, but which affects far fewer people than breast, colorectal, ovarian, and lung cancers.
This is why the NIH designated CLL as the only cancer selected for the TRND project, which invests public funding in new drug development. There are cancers even "smaller" than CLL.
The problem with this is that the US government has a debt crisis, and the TRND project, like many other programs, is threatened by significant budget cuts. Here is the link to TRND:
http://trnd.nih.gov/
http://trnd.nih.gov/?page_id=59 -
3Votesanswered Apr 02, 2011 at 12:03PMKim and Brittany,
I have used the same statistics for the past 2 decades which are for all new drugs. Drugs in phase I have 8% chance of making to the market, Phase II drugs 24% and Phase III drugs 54% probability, NDA filed drugs 75%. These rates were coming down for the past decade. I think the BIO report has more reliable data. I will start using this data, as the data is recent, it will take me some time to memorize. Of course success rates differ with the types of cancer, blood cancer have very high success rates while solid cancer have low success rates. Public funding is influenced by vocal disease and patient advocacy groups and media interest. Breast and prostate cancer have the most vocal and influential advocacy groups. As majority of the anticancer drugs fail, the industry has to select the cancer type based on chances of success and recovering R&D costs. -
3Votesanswered Apr 03, 2011 at 08:50AMHere is the success rate by BIO study data
100 new drugs in Phase I, 63 will go into Phase II, out of which only 21 will enter Phase III trials.
After completion of Phase III, only 12 NDA/BLA will be filed and 9 drugs approved. Only 3 will be commercial success and profitable.
Failure due to toxicity 45
Lack of efficacy 46-
Thanks for the data. Furthermore, I heard from two eminent blood cancer Oncologists that the whole process from lab to application in real life takes an average of 15 years, which may be too late for many with cancer. And not everyone is out of the same "cookie cutter" whereby the approved treatments will work, especially genetic sub-sets of each cancer type. And what about changing the approval process, to get more treatments through. Now, only overall survival and superior efficacy, and not quality of life or palliative purposes are considered.Kim M Robinson commented Apr 03, 2011 at 09:23AM
-
-
1Votesanswered Apr 04, 2011 at 12:04AMKim,
Thanks for your comments. There is worldwide consensus to have safer and more effective new drugs, which translates into long term multinational mega trials to pick up rare adverse effects. This will mean more regulations and increasing safety/efficacy concerns. The FDA and EMA both require robust proof of safety and efficacy in the target population. Industry is reluctant about palliative or quality of life improving drugs. First clinical end points are not clear. There are problems in recovering costs of new drugs which only improve quality of life from insurances and national health schemes. The cost of development is same or even higher as higher number of patients in long term trials are needed to show significant differences in outcome. Only governments can step in and take up the challenge.
Each year about 250 (range 220-300) Phase I trials with new drugs are started. Using BIO study probabilities 157 Phase enter Phase II trials after 1-2 years. Multiple Phase II studies may take 2-3 years. Of these new drugs 52 drugs will go into Phase III which may take 3-5 years. After 1 more year to complete registration dossier, the NDA/BLA is filed for 28 new drugs. FDA regulatory review under fast track, orphan drug takes 1 year and standard review takes 2 year to complete. FDA approves 21 new drugs (in 2010 FDA approved 21 NME). These figures are closer to the overall rates of NDA filing and NME approval during the past few years.-
ThanksKim M Robinson commented Apr 05, 2011 at 07:54PM
-
-
1Votesanswered Apr 06, 2011 at 07:34PMThis article appeared in Medscape News today:
http://www.medscape.com/viewarticle/740273?sssdmh=dm1.678363&src=nldne -
0Votesanswered Apr 07, 2011 at 09:37AMKim,
Thanks for the link to the Medscape story. I had the impression that the accelerated approvals for anticancer drugs was over at the FDA. The life saving drug Ipilimumab for advanced melanoma was not conditionally approved. It took the FDA almost a year to give its green light. BRAF inhibitors like Roche PLX4032 and GSK compound giving 80-90% response in Phase I with tumor shrinkage, should get fast track rapid approvals after Phase I or early Phase II trials. -
1Votesanswered Apr 09, 2011 at 08:32AMThere seems to be some realization at the FDA that approvals move a little slowly for actual patient application, especially considering the minority that make it through the three phases. It has always struck me as sad, from the patient and family member perspective, that the hope in new treatments, not to mention a cure, is often for those far in the future and not necessarily for those who are coping with cancer now. But that is just a "real world" feeling, and I understand the medical and scientific reasons for vetting everything, as necessary for patient safety and efficacy.
-
2Votes
answered Apr 09, 2011 at 02:52PMHow about this as a resolution to the dilemma of attempting to provide therapy or at the least "hope" for those who are "coping with cancer now" vs ignoring their needs and simply looking out for future patients: If a drug SUGGESTS some benefit and free of gross harms in phase I trials, then the FDA should approve this drug which has not shown PROVEN benefit to be made available to current cancer patients who have not responded to previous drugs. The drug should be available at no cost to the patient and at no cost from the prescriber. Why at no cost? Because benefit has not as yet been PROVEN. Once phase II trials proves efficacy, further drug use would no longer be free of all costs. Can anyone show me an error in my dilemma resolution? ..Maurice.-
This seems reasonable, as long as the patient signs a legal consent form that waives any liability of researchers or the drug company.....Kim M Robinson commented Apr 10, 2011 at 11:22AM
-
-
1Votesanswered Apr 10, 2011 at 10:22AMMaurice you are right on target at the present situation for innovative drugs.
The current FDA gold standard for new anticancer drugs remains increase in Overall Survival (OS) in adequate number of patients, which means a few hundred depending on the tumor type. New molecular entities which work in Phase I and II often show reduced efficacy in late stage Phase III trials. Iniparib the first of the new class PARP inhibitors showed 30% response in Phase I trials and 62% in the triple negative breast cancer patients (TNBC) in Phase II trials. Iniparib when added to standard therapy increase OS by 5.5 months on average in Phase II. In phase III trials in TNBC patients, it failed to show any increase in OS. Industry has moved all the follow up PARP inhibitors to more difficult to treat ovarian cancer and bailed out of TNBC trials with these agents.
http://knol.google.com/k/-/-/3fy5eowy8suq3/139#
http://goo.gl/CxTu.qr
A majority of innovative new cancer drugs are small or start up biotechnology companies. The cost of setting up GMP manufacturing facilities run into X times 100 million $. It is a huge financial burden for these companies to pay for clinical supplies for compassionate use. FDA has instituted Compassionate User Program which allows access to innovative drugs after successful Phase II data in Phase III trials and allows companies to charge reasonable costs of production and distribution. Such a use was a huge success with Ipilimumab for advanced melanoma but is not available for BRAF inhibitors as these have only Phase I data. Cancer patients enrolled in clinical trials with new drugs have some chance of cure or tumor regression.
We do not know which drugs passing Phase I and II will pass Phase III without doing the studies. -
1Votesanswered Apr 10, 2011 at 11:32AMI discussed this point with someone I know with cancer, and he made the comment that the overall survival OS criteria inhibits the quality of life factor in drug approvals. He made the argument that a quality of life criteria would "buy time" for cancer patients now, even if the overall survival benefit wasn't as lengthy as hoped for, and in the two or three years of quality of life maintenance, a new treatment might come to be, that would indeed extend the years of life while at least maintaining a comparable quality of life. Or the two treatments might complement one another, as the one has already been "tested". If only OS is considered, that relegates current cancer patients to essentially a hopeless position, if the kind of cancer they have is not measured in the years it will take to reach the approval process end point. Unfortunately, that is the reality of oncology today, and while much as been achieved, much more can be done.
-
1Votesanswered Apr 10, 2011 at 07:02PMKrishan, why does the FDA look only to OS and not to improved quality of life (QOL) with regard to the efficacy of a new drug? Is it because QOL is more difficult to statistically determine compared with OS? Or is it how the pharmaceutical company presents the new drug to the FDA? I mean if the company indicates QOL as the basis for permitting the drug's distribution and use but not prolonging life then would, if the drug was safe, the FDA approve the drug on the basis of improved QOL even if OS hasn't been proven? ..Maurice.
-
1Votesanswered Apr 11, 2011 at 12:59AMThe FDA switch to OS from QOL and tumor shrinkage is fairly recent only about a decade old. QOL criteria are assessed as secondary end points in all oncology trials. Most of the older cancer drugs were approved on the basis of surrogate end points and QOL. Several QOL improving cancer drugs had problems in getting fair reimbursement prices and insurance coverage in Europe.
Who will pay for a new drug which improves QOL parameter by 15-25% and costs >50000 dollars per year. A 15-25% improvement minus placebo response, may be good for the patient but not sufficient for the FDA/EMA, doctor (no clinical significance) or the health insurance coverage.
Nina
Biologics are better tolerated and designed to specifically target the tumor. Monoclonal antibodies, vaccines, r proteins have higher success rates than classical cytotoxic compounds as toxicity is not a major issue for discontinuation. Efficacy trials determine the success or failure of biologics. -
0Votesanswered Jun 12 at 11:43AMI found this very interesting development out of MD Anderson Cancer Center in Texas, about a new approach to Phase I clinical trials that apparently increases the response and survival rate:
http://www.medscape.com/viewarticle/743979?src=mpnews&spon=7 -
0Votesanswered Jun 29 at 10:10AMFrom:
http://www.medscape.com/viewarticle/745347?sssdmh=dm1.698775&src=nldne
It seems that US FDA is speeding up the cancer drug approval process, especially in comparison with Europe. -
0Votesanswered Mar 04 at 10:34AMWhile you are watching all the statistics on clinical trials you can miss the real advances in cancer therapy coming from the world of natural products such as resveratrol, curcumin and salvestrols. These are all natural food supplements that are currently available without the need for clinical trials since they are non-toxic natural products.
The main reason for doing clinical trials is to test new drugs for toxicity, since this is an unknown factor with a new chemical entity (NCE). So new drugs have to go through rigorous clinical trials, and in Phase I this is all about evaluating the toxicity. Natural products such as salvestrols have been in the diet since the dawn of mankind 150 Million years ago. They are now so depleted in the modern diet that cancer is reaching epidemic propertions. My point is that natural therapies that are emerging as beneficial in treating cancer are going under the radar of clinical trial observations.
Sign-in
to post an answer to this question.
Related Questions
- Dupuytren's disease
- What are signs and symptoms of liver disease?
- How do you tell the difference between Hodgkins and Parkinsons clinically?
- Is there a difference between clinical hypoglycemia and hypoglycemia?
- Should terminally ill cancer victims who have failed to respond to all standard treatments have the right to be prescribed and administered drugs which are still undergoing pharmaceutical investigation and are not approved by the FDA for use?
- What are the clinical signs and symptoms of fumarase deficiency?
- What are the opportunities and challenges of translational clinical science?
- What is the efficacy of IgG therapy to help with chronic fungal infections in children (with clinically low levels of IgG) under 10?
- Is clinical acumen a dying art?
- What is the best resource for finding recent clinical trials for parkinson disease?
- »» See All
The content on or accessible through Medpedia.com is for informational purposes only. Medpedia is not a substitute for professional advice or expert medical services from a qualified health professional.
Read more