On June 7, 1999 FDA held a meeting to discuss time to (disease) progression as a standard for drug development. Here is a summary of that meeting I wrote. Report from the Oncologic Drug Advisory Commitee (ODA) FDA meeting June 7, 1999 Topic: Time to Tumor Progression (TTP) as a Possible Basis for Marketing Approval of Cytotoxic Drugs for Initial Treatment of Advanced Metastatic Breast Cancer The current standard for drug approval has been "tumor reduction/response". Since this standard has rarely been effectively correlated to improved or increased survival, some at FDA suggested exploration of TTP. As the committee which consisted of doctors, FDA and NCI staff, consumer activists and scientists talked, they all referred to the GOLD STANDARD meaning improved survival. However, as the meeting progressed, it became clear that this standard has been abandoned, if it was ever used. The following report is meant to be a scathing indictment of the policies used for drug approval. As a caveat, I would like to say that I believe ALL participants are very well meaning-the system is just rotten through and through. A video tape available for $350 is obviously a little too pricey to recommend, but there will be a posted transcript at FDA's website http://www.fda.gov John R. Johnsons, MD, Medical Officer, FDA presented the case against TTP. He said there were two important aspects in looking at a survival effect; toxicity and risk/benefit ratio. He stated that in current trials, there is ordinarily a minority of patients with tumor response which is usually short term. He suggested that TTP would be no better. Drugs need to show a survival increase over no treatment, usually 6 months or more. FDA wants assurance that this gain is not lost. He contrasted TTP to survival as a standard but we do not currently use survival as the standard. He showed that survival is a 100% accurate event, while TTP would be less accurate. Survival is also 100% accurate as to time of event whereas with TTP it would be difficult to determine exactly when progression began since measurements are not taken daily. Survival CAN be assessed daily, obviously. Survival is impartial and is unquestioned, while TTP is subject to uncertainties due to testing constraints and limitations. Survival as a standard also allows both safety and efficacy to be shown whereas TTP is only about efficacy. Survival takes longer to demonstrate. However the survival benefit of a particular treatment may be obscured by secondary treatment, this is true for TTP as well. TTP would require more complete and frequent assessment. This might mean bone scans, chest X-rays, brain CT's etc. Other problems with TTP include possible incomplete assessment at baseline and while being followed. There is also the problem that only observed known disease sites would be surveyed during the trial. If patients die without documented tumor progression, it could mean missed assessments. Additionally patients might only be assessed every two to six months. To accept TTP as the standard, the following possibilities were discussed" - minimal or no survival data needed - accelerated approval with survival data coming later with FDA having the option to withdraw approval - regular approval with survival data coming later with no option to withdraw later To establish a 'surrogate' endpoint such as TTP (non-surrogate is survival directly), there must be either better quality of life or longer life shown. Sandra Swain, MD, ODAC consultant spoke for accepting TTP. She pointed out that only 9 drugs to fight breast cancer were introduced between 1953 and 1974. Then in 1994 paclitaxel was given full approval based on TTP. Docetaxel was approved in 1996 using response rate data. And in 1998, Capcetibine was approved under accelerated approval. (It seems likely that the National Breast Cancer Coalition's actions to raise spending on breast cancer research had a hand in the timing of drug introduction). In 1998, trastozumab (Herceptin) was approved with TTP as the primary endpoint. Time to treatment failure (TTF) was used from the 1970's to the 1990's. It is still used by ECOG (Europe). TTF is calculated from the date of randomization until disease progression or death. She asked if future anti-tumor treatment should be allowed into a study? Dr. Swain then said that survival was easily measured at any time and was the ultimate patient benefit especially if there was good quality of life. She said patients with bone mets alone had a median survival of between 10 and 47 months. She then said the literature suggests only a small survival benefit with our most active agents of 2-6 months. (Ann's emphasis). She also said this 'success" might not be related to the treatment when the patient survives. The problems with TTP are: difficulty in measuring (particularly with bone disease); timing of evaluation which needs to be the same at every testing facility-the tests are often conducted at long intervals; rules are not always prospectively defined, and finally TTP is meaningless if the quality of life is bad and toxic drugs do tend to cause many problems. There is also the problem of confounding influences of continuos treatments, both arms must be balanced. She then mentioned the only trial we have that compared an Adriamycin regimen with CMF, and showed that the TTP was 7 months versus 5 months and survival played out at 19 versus 13 or 16 months (depending on some other factors). She said that if TTP in the studies she looked at showed an increase, then survival was seen to be impacted as well. In discussing these studies, it became clear that survival was never better than 1-6 months overall. Looking at a meta analysis, she showed that of data from 22 randomized clinical trial, 9 had measured TTP or TTF data, 7 had shown comparable survival and 2 showed increased survival (actually TTP was better but survival was similar). Swain showed that a study of vinorelbine with a TTP of one month advantage had a survival benefit of one month. A study of doxirubicin had a survival advantage of 10.5 months versus 9.8 months, and a study of docetaxel showed 2-3 months instead of 2 month survival. The other studies had shown a small advantage but apparently it was NOT statistically significant. Robert Temple, FDA then said that blinded (masked) studies were needed to examine TTP. FDA would insist on survival data and fast track approval should only be given when an advantage was shown, or if the drug was dramatically less toxic. He said since approval for a third line chemo relies on tumor reduction, TTP might be better there. George Sledge, MD said it was hard to show quality of life benefits since most patients were asymptomatic. That meant that many would suffer the "side" or unwanted effects from treatment. If they were symptomatic, some relief might be obtained from treatment. If patients had large, or bulky disease, they might do worse with TTP. There is no striking data favoring TTP and really only one good trial. There is no data relating TTP to quality of life, an extremely understudied area. Investigator bias can affect TTP also. Doctors could make choices of looking at individuals in the treatment arm. RIchard Simons, Dr.Sc. from NCI (statistician) stated that when they looked at an ovarian cancer overview, they saw that partial tumor response did not correlate with survival advantage but when a complete response was obtained, there was usually some correlation with better survival. Robert Ozols, MD, PhD stated that patients want drugs and that quality of life is better if a patient is symptomatic when they start treatment. Richard Schilsky, MD said that if we know patients are NOT progressing at baseline, we know patients who may do well with NO treatment (Ann’s emphasis). Another ODAC member said that the question of when physicians should tell patients they are not benefiting was an important one for quality of life issues. He also said it was important to realize that there was a variability of disease, of doctors and, patients are using alternative/complementary treatments. Temple stated that we had few examples of improved quality of life, indeed it was rarely studied. Sledge said it was difficult to look at quality of life since patients are usually minimally ill or asymptomatic when they join a trial. That is usually part of the criteria, that patients be 0-1on the Karnovsky health status scale, so most are in "good" shape. Temple said that "blinding" or masking in a trial is difficult if the same person is assessing response to questions. He also asked how we can assure that TTP will be measured appropriately? Schilsky suggested an independent review, predetermination as to what constitutes disease progression. At the end of their discussion, ODAC voted NOT to allow TTP to replace current standards. Helen Schiff and Ann Fonfa spoke before this committee stating over and over that increased or long term survival was what patients wanted from FDA drug approval trials. It was pointed out that 2-6 months was NOT considered long term, especially as almost all patients agree that quality of life is NOT improved with treatment. And, unconsidered was the long term effects of treatment. i.e. cardio-toxicity (heart-Adriamycin), or neuropathy (all taxanes), plus many other assorted effects that patients are well aware of. Conclusions: The ODAC group heard what was said and referred to survival as the "GOLD STANDARD" but the disconnect (to use their buzzword) is that survival advantage doesn't seem to be achieved through the current system of drug approval. It has been my contention that our current system only answers the question, "Can this drug be approved?" When a trial is completed, patients don't have much useful information. Oncologists agree for the most part. Dosage levels, timing, and appropriate patient populations are still unclear although there have been literally thousands of studies of cytotoxic drugs (chemotherapy). As was discussed throughout this meeting, we have approved drugs that offer 2-6 months more. Not all patients benefit from chemotherapy. No studies have ever attempted to determine who does from the much larger population of who doesn't benefit. Money talks. Pharmaceutical manufacturers have ZERO motivation to do this type of study. Shouldn't NCI and FDA pick up the slack? It would certainly benefit those patients who do not need chemotherapy and it probably would make it much easier to concentrate on the subset of patients who need more treatment. If we, cancer activists, continue to allow ridiculously low and meaningless standards to be applied to drug development, then we will never get any more useful drugs. New standards need to be applied but they MUST deal with improved survival. And quality of life should be more than buzzwords. There needs to be accurate assessment of what is really going on with patients. New drugs that act differently than cytotoxic drugs probably do need different approval standards. If the anti-angiogenesis drugs pan out, they work by inducing tumor dormancy. How will that be measured in a trial? I recommend that patients and other activists write to FDA to express their concerns. Contact Robert Temple since he sits on the ODAC panel and is head of drug development at FDA. Ask for higher standards, ask for improved survival. Ask for real data on quality of life. And ask for studies to determine who will benefit from chemotherapy so that we can end this blanket administration of cytotoxic drugs which hurt many people while helping a few. IF anyone finds it hard to believe my reporting of this event, I refer you to the transcript of June 7, 1999 ODAC which will be posted on the FDA website.http://www.fda.gov A cancer patient's perspective News coverage of 1999 Testimony from Ann Fonfa and ODAC Committee Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.