Respectful Insolence

I hate it when an article starts right out with a rather annoying usage of terminology, even when it provides information that interests me:

(AP) – Nearly a fourth of widely used new-generation biological drugs that treat several common diseases produce serious side effects that lead to safety warnings soon after they go on the market, the first major study of its kind found.

Included in the report released Tuesday were the arthritis drugs Humira and Remicade, cancer drugs Rituxan and Erbitux, and the heart failure drug Natrecor. All wound up being flagged for safety.

That might surprise some doctors who may have thought that these new treatments might be safer than traditional chemical-based medicines.

I guess what I dislike here the use of the term “chemical-based medicine.” After all, all medicines are chemical-based, because they are chemicals. It’s just a pet peeve of mine. I realize what the writer is referring to is the new generation of drugs, which have been referred to as “biologicals.” A lot of these new drugs are antibodies against specific biologically active proteins generated through monoclonal antibody and recombinant DNA technology. The idea is that they would be more specific and have fewer side effects because they target usually only one protein. At least, that’s the idea. Perhaps there was a bit of naivete among physicians in believing that these drugs would be less likely to pop up with unexpected toxicities after release, but such was the hype surrounding this new class of drugs that this belief was widespread. It wasn’t entirely unjustified, either. A lot of these drugs are incredibly precise in their effects.

However, if there’s one thing biology teaches us, it’s that interfering with the function of even a single protein can have unexpected and wide-ranging effects. Because our understanding of the biology is nearly always incomplete, the extent of such side effects and adverse reactions are often difficult to predict. Indeed, the tendency of nonsteroidal antiinflammatory drugs to cause stomach bleeding is not immediately obvious from their mechanism of action.

Curious, I looked up the study referenced in the news report above. Coming from a group of Dutch researchers, the study was published in the Journal of the American Medical Association and is entitled Safety-Related Regulatory Actions for Biologicals Approved in the United States and the European Union.

The problem with the approval of these new drugs is described in the introduction:

Knowledge of a new drug is incomplete at the time of approval, especially with reference to its safety profile, due to a variety of factors including constraints in the sample size and the design of randomized controlled trials.6-7 Although this also applies to small molecules, biologicals carry specific risks. In contrast to small molecules, which are synthesized chemically, biologicals are derived from living sources (eg, humans, animals, cells, and microorganisms). The production and purification process of biologicals is more complex, involving numerous steps with the risk of influencing the characteristics of the end product at any single step in the production cascade.8-9 Small differences and changes in the production process can therefore have major implications on the safety profile of biologicals. For example, the incidence of pure red cell aplasia in patients treated with recombinant human epoetin, an extremely rare complication induced by antibodies, was elevated in patients taking one particular formulation of recombinant human epoetin in which human serum albumin was replaced with polysorbate 80 and glycine.10-11 However, the exact mechanism underlying the increased risk of pure red cell aplasia after the formulation change is not yet fully understood.12 The risk of contamination with pathogens by the donor is another problem related to the production process (eg, for products extracted from human blood or plasma).13

Biologicals are specifically prone to the induction of immunogenicity. In many cases, the consequence of immunogenicity is not clinically relevant. However, in some cases immunogenicity can lead to loss of efficacy of the drug or, even worse, lead to autoimmunity to endogenous molecules. There can be a major clinical impact if a natural protein with essential biological activity is neutralized by antibody formation.8, 10, 14-15

In other words, biologicals are more difficult to make, more prone to lot-to-lot variability because they are often proteins, and they have a tendency to provoke an immune response. True, there are lots of molecular “tricks” that can be used to reduce the likelihood of provoking such unwanted immune responses. One is to “humanize” the antibody by taking the parts of it that recognize and bidn to the protein it targets and hooking them onto the “backbone” of a generic human IgG antibody. This is accomplished by merging the DNA that encodes the binding portion of a monoclonal mouse antibody with human DNA coding for antibody. Mammalian cell cultures are then used to express this DNA and produce these half-mouse and half-human antibodies, which are not as immunogenic as the mouse variety. Indeed, one of my favorite such drugs, bevicuzimab (otherwise known as Avastin), which targets an angiogenesis-stimulating protein known as vascular endothelial growth factor, was produced this way. As for other classes of biologicals, some are hormones; others cytokines, others growth factors, but most are proteins and thus share the problem of immunogenicity.

Another aspect of this is not specific to biologicals, and that’s the process by which drugs are tested before being approved. It is financially impossible to test all drugs on numbers of people huge enough to detect uncommon adverse reactions and side effects. Most pharmaceuticals in phase III trials are tested in a few hundred or, at most, a few thousand subjects before being released. Drug testing is already incredibly expensive and difficult; so it’s simply not feasible to test a drug using more subjects in most cases. Moreover, the population of subjects in clinical trials is not always generalizable in terms of side effects and complications to the population treated. Often, they tend to be healthier, because of the selection criteria of clinical trials designed to make the different experimental groups as similar as possible. Consequently, when drugs are approved, post-approval monitoring is important, because when a drug is suddenly used in many thousands, even millions, of people, suddenly uncommon or even rare complications can become an issue.

Basically, what this study showed was simple. First, out of 136 biologics approved in the United States and 105 in the European Union between January 1995 and June 2007, total of 41, or nearly 24%, provoked safety warnings issued through June 2008. Second, “first in class” biologicals (meaning the first biological targeting a specific protein) were more likely to provoke a safety warning. It’s hard to estimate, but these appear either somewhat higher than or equivalent to the percentage of “chemical” drugs that provoke such warnings after FDA approval. One reassuring observation was that the vast majority of these safety problems were identified soon after the biologicals became available. Another is that none of the safety concerns were severe enough to result in the removal of one of these drugs from the market. On the other hand, this study is based on a relatively small number of biologicals, and these agents are still pretty new, which means that it’s unclear whether this will be the rate of problems in the future. There is, after all, a “learning” curve, and it’s quite possible–even likely–that we’re getting better at designing and testing biological agents. Time will tell.

As the authors state:

Some of the biologicals (for example, monoclonal antibodies) differ essentially from naturally occurring substances and might therefore be especially susceptible to adverse drug reactions. Although the 95% CIs were broad, our study confirmed that these and other biologicals, including cytokines, growth factors, interferons, and receptors were specifically prone to safety-related regulatory actions. Within the group of monoclonal antibodies, the murine antibodies had a lower risk for a first safety-related regulatory action compared with the humanized monoclonal antibodies. However, this finding should be interpreted with caution due to the small number of monoclonal antibodies and safety-related regulatory actions.

The conclusion:

Warnings issued in the system organ class of infections and infestations were often related to the immunomodulatory effect of many biologicals. Although the limitations of preclinical trials for biologicals are acknowledged, results from pharmacology studies, preclinical studies, and clinical studies might result in the prediction of potential risks related to the drug for which close monitoring is needed in the postapproval setting. Health care professionals should be aware of the specific risks related to the relatively new class of biologicals to be able to provide a link between the use of the biological and the patient presenting with a clinical problem. In addition, the classes of antibodies (monoclonal), cytokines, growth factors, interferons, and receptors and the first biologicals approved in a chemical, pharmacological, and therapeutic subgroup are specifically prone to a first safety-related regulatory action; close monitoring of these biologicals is therefore recommended.

New biological agents are proliferating, as well they should. They show great promise of improved treatments for various diseases and conditions with lower toxicity. However, they are not panaceas and do have potential adverse affects that may not be obvious from mechanism of action, although that might be predicted better as we understand the biology better. Also, one thing I particularly like about this study is the way it shows that science- and evidence-based medicine represents a self-correcting, self-monitoring system that does detect adverse outcomes.

Can anyone picture a naturopath doing a survey like this?

Comments

  1. #1 Calli Arcale
    October 22, 2008

    I can’t picture a naturopath doing such systematic research, but I can forsee them enjoying this study for all the wrong reasons. I suspect they will particularly enjoy this passage:

    Some of the biologicals (for example, monoclonal antibodies) differ essentially from naturally occurring substances and might therefore be especially susceptible to adverse drug reactions.

    See, natural stuff is safer!

    Of course, they will overlook a) what exactly is meant by “naturally occurring”, b) that many naturally occuring substances are downright lethal, c) most pharmaceuticals are naturally occurring substances, and d) it was mainstream medicine itself that raised this concern, because unlike alternative medicine, mainstream medicine tries not to blind itself with pride.

    Hmmm…. I wonder if any of them will encounter cognitive dissonance with a distinction made between “biological” and “naturally occuring”? It makes sense in context, but might be confusing to quote-miners and study-skimmers.

  2. #2 Helblindi
    October 22, 2008

    Orac, can you think of a reason why this research does not cover vaccines?

  3. #3 Orac
    October 22, 2008

    Vaccines are intensively monitored post-release for unexpected side effect not detected in the clinical trials that lead to FDA approval. There’s the VAERS reporting system, the VSD Safetylink database, and other mechanisms to detect adverse reactions; so I’m not sure what your point is, other than to imply that vaccines are somehow held to a double standard. They’re not. If anything, because they are given to healthy children to prevent disease, they are held to a higher standard.

  4. #4 Helblindi
    October 22, 2008

    I’m not implying anything. I know next to nothing about this line of research and while browsing the paper I noticed vaccines among items explicitely excluded from the study – so I decided to ask somebody with the knowledge why. No malicious intent here.

  5. #5 Calli Arcale
    October 22, 2008

    I think it’s because they were looking at the difference between the new “biologic” drugs and older drugs — vaccines would have been beyond the study’s scope.

  6. #6 Abel Pharmboy
    October 22, 2008

    I’m surprised they only detected one-fourth of the drugs as having unforeseen adverse effects only after approval. This great 2005 NEJM paper by Susan Okie, MD, cites a report that this is true of about half the drugs. It’s behind a firewall but here is the intro:
    In most cases, when a new drug is approved, almost everything known about its safety in humans is based on the responses of a few thousand people who took it during clinical trials. But once the drug is on the market, the real safety testing gets under way. Within a year or two, the number of people who are exposed to the medication may climb into the millions, especially if the manufacturer promotes it aggressively with television or print advertisements that target consumers. If the drug has a dangerous but rare side effect — for example, liver failure or aplastic anemia — that occurs in fewer than 1 in 1000 patients, that effect will generally be recognized only after the medication is being widely used. Moreover, if the drug increases the incidence of a common condition, such as myocardial infarction, that risk, too, is unlikely to be identified until millions of people have taken the drug. About half the drugs that enter the market have serious adverse effects that are detected only after approval.

    And these days, more often than not, Americans are the test population. Fifteen years ago, most new drugs were first approved in other countries. If life-threatening side effects showed up after approval, the products never made it to the U.S. market. Today, because of speedier review of product applications by the Food and Drug Administration (FDA), more than 60 percent of new drugs are approved first in the United States.

    We really need to do a better job of teaching the public that “absolute safety” does not exist for drugs, or for anything else for that matter (like automobile driving, for example). The FDA plays the unenviable role in the US of trying to get new drugs to people who need them as quickly as possible while minimizing the risk to the largely population. Every time one takes a drug, one is making a risk-benefit decision.

  7. #7 Abel Pharmboy
    October 22, 2008

    Postscript: The above pgh beginning with, “And these days,” should also be italicized as it is pgh #2 of the aforementioned NEJM paper.

    The last pgh is mine.

  8. #8 Orac
    October 22, 2008

    No malicious intent here.

    Sorry. I noticed this morning that the antivaccine blog Age of Autism was hyping this study and asking why it didn’t apply to vaccines; I jumped to the conclusion that you were parroting that post.

  9. #9 leigh
    October 22, 2008

    that’s the price we start to pay when we switch from (relatively) simple chemical structures to macromolecular medicines. more specific targeting requires more complexity by the sheer amount of information the drug must possess, it’s also introducing new ways for the drug to cause side effects.

    another classic case of “the more you learn, the more you realize you don’t know anything”

  10. #10 Kemist
    October 22, 2008

    So… There will still be a use for synthetic chemists yet ? ;>)

    Actually, thanks to innovative synthetic techniques, some synthetic peptides/nucleoside are starting to be more marketable. Synthetic vaccines are almost already upon us, pioneered, believe it or not, by Cuba. This could solve the problems that are due to conventional vaccine production (which are made with eggs), namely, that people allergic to eggs cannot receive them and that it’s almost impossible to produce a vaccine against avian flu viruses (which kill eggs).

  11. #11 The Perky Skeptic
    October 22, 2008

    Interesting. A relative of mine was treated with Rituxan. I hadn’t really considered all the ins and outs of monoclonal antibodies and other biologicals. Hooray for science-based medicine, with its studies and safeguards and followup! (Also, I am having a hard time typing… I think I am a little high from my flu shot. Now, THERE’S a side effect! ;D)

  12. #12 Lora
    October 22, 2008

    Um, this might be a bit stupid, but…The problem with biologics is that they tend to be immunogenic, yes? They provoke a Th2 response from the immune system, which can lead to autoimmunity because most biologics have similar epitopes to self proteins.

    The whole point of vaccines is to induce an immune response in the patient, correct? The epitopes in vaccines aren’t usually anything at all like human proteins, and the most immunogenic epitopes are those that are furthest from any human epitope–so those are the proteins chosen for vaccine development. If they did look like a human protein, they wouldn’t be very good at generating an immune response in most people.

    So why would immunogenicity be a flaw in vaccines again?

  13. #13 Brian
    October 22, 2008

    That’s what happens when you confuse specificity with selectivity.

  14. #14 Annie
    October 22, 2008

    I’ve been lucky enough to have been on several of the biologicals mentioned, and have two good friends on Rituxin. Thank you for pulling out the worthwhile reading, it gets hard for a novice to sludge through every report to get to the important parts. Couple points.

    This is part of the argument preventing the biological Enbrel (10 years on the market) to reveal its recipe so it can be generic. “To complicated to make and easily contaminated.” So I was happy to read it in a scientific paper rather than Enbrels defense marketing. The four I have used are very expensive even with excellent health insurance. I pay $500 for 2 months worth and that is just one medication. Sadly they’ll never drop the price if there is no competition.

    The “chemical” meds vs Biological meds isn’t really relevant as if you are on several of the “chemical” meds and they don’t stop the disease, a biological is your only resort. I am three chemicals-Methotrexate, Arava, and prednesone (finally tapering off) and still need Humira weekly. Without that biological I couldn’t wipe my behind, let alone dress myself. My good doctor explained, and I read all the possible dangers, which aren’t that much different from Methotrexate and I’ve been injecting that for years.

    These medications are a miracle for the inflammatory arthritis people and there are many that can’t afford the option of using them. I believe those clinical trials get filled up quick, unless they are looking for newly diagnosed or non pred people.

    Finally, interesting “However, in some cases immunogenicity can lead to loss of efficacy of the drug”, as several buddies swear that Remicade is useless one time and works great the next time they need it. They have not found a way to confirm. Unlike my Humira, which I inject myself, they can’t even get the nurses to let them monitor the batch numbers. They suffer terribly (with joint damage) until the next allowable dose, at least a month later. If they could confirm this problem (like water), they could get another dose sooner.

    Many of us have also developed immunity to the drugs and they no longer work, so we pile on additional medications and wait for the next one to make it to the market. Hurry, I say.

    Hey, anti vaccine people, you could kill me.

  15. #15 Schwartz
    October 22, 2008

    “Drug testing is already incredibly expensive and difficult; so it’s simply not feasible to test a drug using more subjects in most cases.”

    That’s a pretty good cop-out if I’ve ever heard one. Why is it sometimes feasible and other times not? I think it’s feasible if required by the FDA. Large population, long term studies are do not have to be restricted to phase III trials, they can be performed post approval, yet we know that the majority agreed upon post approval trials are never completed properly per the FDA. This is well documented and clearly needs to be rectified.

    “Moreover, the population of subjects in clinical trials is not always generalizable in terms of side effects and complications to the population treated. Often, they tend to be healthier, because of the selection criteria of clinical trials designed to make the different experimental groups as similar as possible.”

    While I agree completely with the first statement, I strongly question the accuracy of the second. While phase I and II trials are often performed on healthy adults, Phase III trials are almost always performed on adults afflicted with a disease or condition for which the drug is designed to treat. By definition, they are not healthy. In fact, in my experience, these candidates are usually recruited by specialists who run clinics that these sick individuals have been referred to and the candidates are are often quite unhealthy. I am curious why you think phase III trials are most often run on healthy adults or perhaps I misunderstood what you’re trying to say?

    Your comments on the importance of post approval are quite valid, so I would ask the question of how good the post approval monitoring is done in the US since I don’t know.

    “Also, one thing I particularly like about this study is the way it shows that science- and evidence-based medicine represents a self-correcting, self-monitoring system that does detect adverse outcomes.”

    Science itself may be self-correcting, but medicine and governmental organizations, along with scientific ones, contain all of the faults that come along with human nature, and thus it is a shame that your ideal statement doesn’t provide much comfort. There are significant faults in the system, which have been identified for years without any corrective action being taken. That is not scientific, nor self-correcting.

    “-that we’re getting better at designing and testing biological agents”

    I think you should add manufacturing/production to this as well. If some of the problems involve production consistency, then I think that these could improve over time. Included in production is post-production testing which could better detect inconsistencies out of acceptable ranges and remove those from the pipeline allowing us to maintain higher quality product. Especially since I agree some of these compounds show such high promise.

  16. #16 Annie
    October 22, 2008

    The problem with the trials of at least some of the biologics is, most patients are already being treated for the disease with another medication or medications. So, do you have them stop what they are on to test the new drug? or keep them on the medications add the new one and worry about drug+drug complications, along with possible complications of the new drug? So at least for the ones I monitor, they look for people who aren’t on any medications or have failed most or all the medications. If you are brand new to the disease, why would you try something iffy when there are some tried and trues to use? If you have failed most of the medications you are frequently in pretty bad shape and aren’t interested in showing up weekly and devoting hours of your time when you can barely get out of bed and still have to work and try to have a life.

    That leaves the people without health insurance who will gladly sign up for trials, who sadly have unnecessary damage due to inability to pay for medications.

    I wonder about improved production with these considering they are mouse, hamster or human cells converted to a new use. Would be great though because then there would be generics.

  17. #17 CanadianChick
    October 22, 2008

    what Annie said!

    I’m on Enbrel 2x/wk and my doctor made sure that I realized what I was getting into. But, while I ardently dislike my increased susceptibility to infections (or at least what I believe is increased susceptibility, could just be an assumption on my part) I really like being able to walk.

    Schwartz, drugs like Enbrel are really expensive. In Canada, where drug costs are usually lower than they are in the US, my Enbrel costs about $1400/month. And that’s the price while they’re in full production mode – I can only imagine how much it would have cost during trial stages. So, I can understand that there might be a cost factor to consider in determining the number of subjects for trials.

    Plus, as Annie mentioned, it is DIFFICULT to find people who need this class of drug who aren’t on a bunch of other meds, who don’t already have permanent joint or organ damage, etc etc…

    I’ve looked into participating in clinical trials before, but generally speaking, they’ve wanted me to discontinue all my meds except for the trial drug. I need to go to my job every day – I’m not willing to give up my daily Celebrex and weekly methotrexate (and risk being housebound) for the thrill of trying a new drug for six months.

    Now, back when I was first diagnosed, in my early 20s, and had moderate disease, I probably would have been willing to give it a shot. Now, almost 40, no way in heck will I participate in anything that asks me to give up my celebrex and methotrexate.

    I doubt I’m the only one.

  18. #18 Schwartz
    October 23, 2008

    CanadianChick,

    People in clinical trials don’t always have to pay for their drugs.

  19. #19 Kathryn
    October 23, 2008

    Schwartz,

    I think CanadianChick was using the only cost figure she has to give some idea of the scale of the manufacturer’s cost to produce biologicals for larger trials before the production line is set up.

    Presumably, during trials, the company has a lab full of people with PhDs (or at least masters’ degrees) growing cultures and isolating the drug in small batches. These products take time to produce. There might even be a factor of how many people will it take to make enough for all the patients in the study to get their doses.

    Does anyone here work in the field and have a better understanding they can present?

  20. #20 symball
    October 23, 2008

    @ Kathryn,

    even before trial there has to be a consistent scaled production method for making biologicals. I’m afraid that instead of PhD’s or even BSc’s the staff are likeley to be (admittedly above standard) ‘joe sixpacks’ or the equivalent female term (josephine wineglass? jenny rumNcoke?)

    all drugs must be tested in pre- clinical tests (animal studies) using the same method that is used in the final formulated product, and any changes to this formulation later mean that the pre-clinical and clinical trials have to be repeated. Before a clinical trial drug is approved by the regulators it has to have been produced three times with identical end products or it will not be allowed to be used.

    @ Annie
    where there is a risk to patient safety by dropping their current treatment a drug company will do one of two things in a clinical trial. 1) perform the trial with the drug and compare it to patients on the drug only to see if there is an improvement (alongside the risk of drug- drug interactions) or 2) perform the trial in a country where there is a high population of untreated individuals (eg, india, china or africa)

    For a drug to be licensed you will have to show an advantage over current treatments, otherwise you will get no usiness anyway, the majority of clinical trials now are looking at generics- almost identical copies of off patent drugs that can be sold for a fraction of the cost because the research has already been done.

  21. #21 Annie
    October 23, 2008

    Symball, I am only going by the clinical trials I follow–in case I can sign up, or so I know when they will get to market. I understand that they don’t want you on other drugs, I understand completely, unfortunately, that knocks me and most other sufferers out of the trials.

    The trials I follow are in the US. Though there is no cost to test them, physically, the cost of stopping MTX and Humira and getting to doctor office frequently is very very high. If your wrists are partially damaged already or your ribs are partially fused, would you gamble to try something new? Humira only partially works, and its my third time on it, I am waiting impatiently for the next biological to come out. I am on very high dose MTX (40mg) and Arava at the same time. Being on both, I have all the symptoms of chemo, hair loss, nose/mouth sores, nausea/vomiting. I take two drugs to combat them, I am also on pred and take osteo IV meds to prevent any more bone fractures. Its still worth being a functioning human being.

    I have never gotten sick yet in 5 years, but if I would, I would have to stop all meds for months and it takes much longer to get well. So catching the flu from someone would mean torturous rib pain while having flu symptoms and watching your wrists turn into mush, forever. Think about that next time you sneeze on someone.

    Bring them on the market, and work towards generics.

    Annie

  22. #22 trrll
    October 23, 2008

    That’s a pretty good cop-out if I’ve ever heard one. Why is it sometimes feasible and other times not? I think it’s feasible if required by the FDA.

    Biologicals typically require i.v. administration, which drives up the cost of clinical trials substantially. They may be expensive to produce, particularly early on when there are no economies of scale.

    Of course, the FDA can always require larger clinical trials. But the Pharm manufacturers will then have to take that into account in their net present value calculations that dictate where they will invest their research dollars–so they will be less willing to develop biologicals, particularly those for which there is a smaller market, or less probability of success, or for which it will not be feasible to charge very high prices.

  23. #23 daedalus2u
    October 23, 2008

    The problem with all of these biological products is that they don’t do only “one thing”. Nothing in physiology only does “one thing”. A physiological pathway can’t evolve to do only “one thing”.

    The way all pathways evolve is by taking an existing pathway and elaborating on it. Sometimes that means duplicating the gene, then the redundant gene can mutate so it can do something extra. Sometimes it loses some of its former activities, sometimes some of those activities are simply degraded. Many pathways go back a billion years or more. They have been being elaborated on for a very long time.

    Taking Epo for example, there is nothing simple about erythropoietin.

    “Erythropoietin (EPO) gene expression is under the control of inhibitory (GATA-2, NF-kappaB) and stimulatory (hypoxia-inducible transcription factor [HIF]-2, hepatocyte nuclear factor [HNF]-4alpha [alpha]) transcription factors.”

    http://www.ncbi.nlm.nih.gov/pubmed/17998055

    If it was doing just “one thing”, it wouldn’t need such a complicated control system.

    It is regulated in multiple tissue compartments in utero and ex utero under quite different O2 partial pressures by transcription factors that activate or deactivate hundreds of other genes. It does multiple different things. There must be sufficient degrees of freedom in the control system that regulates Epo to regulate it appropriately for it to function appropriately to do all the different things it does in each of the different tissue compartments it does its thing in over the human lifespan.

  24. #24 Lora
    October 23, 2008

    “all drugs must be tested in pre- clinical tests (animal studies) using the same method that is used in the final formulated product, and any changes to this formulation later mean that the pre-clinical and clinical trials have to be repeated.”

    Eh…Sorta. In practice, you can make small changes as needed while you’re scaling, and you actually do two formulation studies: you submit your initial Phase I using your pre-formulation data, and it’s understood that you may have to tweak it a little. Pre-formulation is mostly just what buffers you are using and a conservative estimate of storage conditions using some folding studies. What really counts is that your end products have 100% identical sequence, posttranslational mods, bioassay results etc. For this reason, you don’t want to make several small batches, you want to make one or two big batches. If you can, best thing is to use Batch 1 for reference material, preclinical & tox studies, then use Batches 2 & 3 for the actual clinical work.

    Otherwise you have to bank a LOT of cells, and believe me, cryostorage freezers are bloody expensive to maintain.

    @ Kathryn: “These products take time to produce. There might even be a factor of how many people will it take to make enough for all the patients in the study to get their doses.”
    It depends on your awsum engineering skillz. ;) Actually, when you’re scaling up it’s easier to make a lot more than you’ll need, provided someone upstream of you has handed you a reliable cell line with good parameters. It’s a setup thing–it’s a big time and $$ investment to start up a reactor, but once it’s going it’s easy to maintain. And it depends on if you’re using fixed equipment or disposables, as the disposables are easy-peasy lemon-squeezy to run.

  25. #25 Schwartz
    October 23, 2008

    Kathryn,

    “I think CanadianChick was using the only cost figure she has to give some idea of the scale of the manufacturer’s cost to produce biologicals for larger trials before the production line is set up.”

    I may have misread her intent. In that case however, the cost of a drug is definately not reflective of the cost of manufacture ever, but expecially pre-patent expiry. The cost of drugs are reflective of supply and demand. If a single company controls the supply of a drug, and there are no competing drugs, then they can charge as much as the market will bear for such a drug. Of course, demand size matters as well, because if it is a mass market drug, then they can re-coup the research costs and spread them over a wider group of people. The bottom end cost may be related to manufacture costs after there is competition, but certainly not before that point. The recent jump in the price of Thalydomide is a prime example of the disconnect between price and manufacture costs.

    We also have to remember that difficulty in manufacturing actually works in favour of the pharmaceutical because the manufacturing process can be patented, and if it is difficult, this could easily add several years onto the effective patent protection of the drug and would significantly raise the barrier to entry for a competitor or generic.

    Trrll,

    I don’t think feasible is the right word. Pharma will make the clinical trial the minimum size required in order to maximize profit as I would expect. Feasibility has nothing to do with it. Regulation determines the minimum size, and profitability drives the behaviour.

  26. #26 Jacob Schor ND
    October 27, 2008

    You asked whether “Can anyone picture a naturopath doing a survey like this?”

    I certainly could. Any decent practitioner will look to measure outcomes of treatment in any manner possible in order to revise protocol and strategies to obtain optimum results. The problem is not the type of practitioner, anyone with half decent training in biological sciences and scientific method will approach medicine rationally. The problem is when ego clouds judgment and the need to categorize information to simplify complex systems blinds one to the truth.

    Jacob Schor, ND

  27. #27 Lucario
    November 2, 2008

    Reading about the horrors of getting autoimmune diseases and the high cost and terrible side effects of treatment worries and sometimes scares me. Is there any way to prevent myself from getting these diseases, like there are ways of preventing (for example) heart disease? I don’t want to end up being a burden on my family.

  28. #28 none
    November 2, 2008

    Treat Cancer with Flavonoids!

  29. #29 daedalus2u
    November 2, 2008

    Lucario, autoimmune diseases are virtually unknown in the rural undeveloped world. There is an idea, called the hygiene hypothesis that there is something about being dirt poor and living in dirt and eating dirty things that keeps you healthy. It isn’t just autoimmune disorders that are unknown, diabetes, obesity, heart disease, kidney failure, are all very rare.

    I think that the protective agent is the bacteria that I am working with, the ammonia oxidizing bacteria. On the external skin they metabolize ammonia in sweat into NO and ntirite and by doingn so set the basal NO/NOx level. This is important in immune system regulation via NFkB, in energy status by regulating ATP and mitochondria biogenesis, in hypertension by regulating vascular tone, in endocrine disorders by regulating steroid synthesis.

    One of the first things that development brings is abundant clean water with which to bathe. This washes off the bacteria faster than they can proliferate and the body then loses that pathway for regulating NO/NOx.

  30. #30 Lucario
    November 7, 2008

    So, how can a person living in a developed country get all the health benefits of being dirty and eating dirty things without a) having to go to some gods-forsaken third world country and b) maintaining a modicum of social respectability (i. e. not being stinky)?

    Also, I’m 32 going on to 33 in a few months. Is it too late for me to start?

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