Vertex - what about the data from the 12 weekers?

Hi Everybody,
As I am closing in on the end of my 12 week VX950 treatment I find myself wondering about the deafening silence regarding the 20 x 12 weekers on the PROVE1 trial.  I would like to think that I would be informed about the progress of that trial arm before I am cut loose from treatment myself.  Irrespective of the original trial protocol, it would not be ethical to let my trial arm stop treatment if, for instance, Vertex already knew that the PROVE1 12 weekers were having a significant relapse rate.  Or does the silence mean that Vertex has data which gives reason to be confident that 12 weeks does the job but they don't want all the other arms to abandon treatment early?  Isn't there a case for Vertex being morally obliged to reveal this data to us PROVE2 12 weekers and offer us ongoing SOC if our prospects don't look good?  As mremeet says - there's plenty of sport in these trials.  Anybody got 2 cents worth on this?
Thanks,
dointime.              

[jmjm530]

I do not think you can draw any conclusions except that Vertex is keeping those results close to the vest probably for a number of reasons. Also, the fact that th 12 weekers had a hypothetically high relapse rate does not mean that the 24 weekers would. Also, let's say that the 12 weekers are doing quite well for only 12 weeks -- let's say 50 per cent stayed non-detectible -- they still may not want to release those numbers hoping for better percentages from the 24 week group. I agree though that it would be nice if those numbers were released but I'm sure there are lots of forces at play. Within the year we should have the full story.

[jmjm530]

Maybe I read your post wrong. Are you saying that you're only doing 12 weeks of triple thereapy (Vx, peg, riba) with no SOC after that? I figured you were in the 24 or 48 week group.

[jmjm530]

Sorry again, easy to get these trials confused. You're in the European 12 group trial if I now remember correctly? And apparently the European 12 weekers started later than the American 12 weekers (Prove 1). So if I'm correct so far, than you'd like to know how your American counterparts faired who should have already collected some post tx vl data, maybe even post tx 3 month data by now. So, yes, if I were in your shoes I'd be anxious to know how my American counterparts did as well! And yes, I think it would be unethical to let you stop at 12 weeks if say there was a significant relapse rate in the American 12 week group. But what if the relapse rate was 50 per cent like it is with SOC. Would they pull the plug on the Prove 2 12 weekers. I really have no idea, but if I had little or no liver damage I'd be happy to be in either the 12 or 24 week group as opposed to the 48 week group. Maybe your trial doctor can make some calls to his collegues in the U.S.?

-- Jim

[mremeet]

All I know is that Vertex is scheduled to make some kind of presentation at the European Liver Conference(?) in Barcelona in mid-April. Whether they will show their 12 week cards at that time is anyone's guess. I certainly know we've all been wondering about that. And not only the Prove 1 twelve week group, but the original group of 12 people in phase 1 that received VX+SOC for 4wks followed up with 44 more weeks of SOC. That trial started well over a year ago, so where's the data on them?? That's another one we've been wanting to find out about, hopefully they'll come clean on that info at the conference too.

Otherwise the only shred of "evidence" I can think of that may pertain to your situation in any way, unfortunately would be Travelmom's experience. She was in prove 1 and started out with an intolerance to riba. She stopped the riba at day 4 because of a bad rash, but continued on with VX and IFN. After 12 weeks she stayed on IFN alone for another 12 weeks. Unfortunately the virus had a breakthrough at week 16, although she was initially UND by week 3-4. Of course this doesn't mean this is what will happen to you, she's only a singular example, and therefore no extrapolations could be made to anyone else's performance. But she was a pretty typical HCV case, starting VL of 4 mil, no cirrhosis, and she did manage to become UND in less than 4 weeks. So she did respond initially and was doing ok. But in the end it was not to be. Her experience makes me vaguely suspicious the riba may play a larger role than we had all hoped (even if a PI is used in its place) - with the possible exception of those with very low starting VL's.

Anyway, wish I knew what to tell you. This watching, waiting, blinded thing is a real mind f**k, isn't it? Whatever happens, wishing you the best, hang in there.

[jmjm530]

I'm not sure TravelMom's experience is any more pertinent to the 12 weekers than those that are still non-detectible after 12 weeks triple and 12 weeks SOC. In other words, really nothing to gauge the likelihood of response to 12 weeks of triple therapy IMO. Like you said, TM had to stop riba at day 4, so hard to really compare her with anyone. My thinking is that if the 12 weekers in the U.S. had a very high relapse rate, they wouldn't let the European 12 weekers stop, but maybe I'm being naive. I do believe data has been released at the recent AASLD on that original 12 week group but not 100 per cent sure.

[pln]

Day 1 pre dose - 2,280,000
Day 4 - 229
Day 8 - 29
Day 15 - 29
Day 22 - < 30 UND
Day 29 - < 30 UND
DAY 43 - 29
DAY 57 - 29
DAY 71 - 29
DAY 85 - < 30 UND
DAY 85 POST DOSE < 30 UND
WEEK 16 - 157
WEEK 20 - 131,000

This is Travelmom's VL from vertex, she had lots of breakthroughs. she had no riba, maybe the wild type of virus we were reading about? I sure (hope) we will hear soon.

[mremeet]

The reason I used Travelmom as the vaguest basis for comparison was because dointime is going 12 weeks sans riba.

[jmjm530]

Ahhhh. Didn't realize Prove II had a 12-week group without riba. So the question then becomes how much did the riba play in TM's case or was it just coincidence? So what's your opinion on Vertex going ahead with the Prove II, 12 weekers without having decent numbers on the still undisclosed 12 week Prove I group? I'm thinking maybe the Prove I 12 weekers had decent (maybe 50-70 per cent) numbers but they don't want to release because they're looking for maybe 80 per cent which they hope they will get with the 24 weekers. All speculation of course. Another possiblity is that it was mandated that these Prove I and Prove II trials be totally separated so it's possible that the Prove I data cannot be used to alter Prove II protocols. Really don't have a clue what's going on behind those doors.

-- Jim

[mremeet]

I think if Vertex has sufficient Prove I data on hand to reasonably know that the apparent response rate of 12 weekers WITH riba is not so hot, then I think they have an obligation at this point to commute the Prove II 12 week group "sentences" to 24 or 48 weeks total (transitioning them over to riba+INF after the first 12 weeks). To do otherwise would be unethical, especially considering the likelihood that a short and unsuccessful course of VX + IFN could saddle these 12 week people with a drug resistant strain, thereby lessening their odds of successful treatment in the future (possibly even with access to telaprevir again).

Otherwise I have no idea how successful the 12 week group was (or will be). But listening to Boger, you get the impression they did great. Although based on some of his speeches, he seems to take the salesman rhetoric a bit far at times, so in my view that makes his credibility somewhat suspect. That is, until I see some real hard SVR data to support his optimism.

[jmjm530]

Certainly would be a blessing if twelve weeks can do the trick for geno 1's -- with or without riba. Let's keep our fingers crossed.

-- Jim

[pln]

Hey, The reason I posted travelmom's vl report was to let you know she had lots of breakthroughs, and this is not typical of vertex from the reports we have seen so far.

So do not give up hope you very well might have cleared at day 4 like myself, and stay that way FOREVER!

[dointime]

Great to get your comments on this guys.  Thanks to you and travelmom for letting me know about her experience which I think is very relevant to my situation.  If I am in a position to make choices about further treatment I'll be sure to say I want riba added to the mix, much as though I find the mere thought of doing riba repellent.  

Everything in me is saying that I want to be done with this drug regime at 12 weeks - that is assuming I am UND at 4 wks and 12 wks with no breakthroughs.  However, logic tells me that my best chance of SVR, given the possibiity of relapse and ending up with drug resistance, is to continue on treatment for longer if I am offered that choice.

Watch this space .....
dointime.      

[Kalio1]

I just wanted to thank you for your well thought out and succinct analysis.
I think you make a VERY good point about the internet and it's impact on trials, all trials not just the VERTEX trial. What an problem that creates for them! I think you are dead on in saying it would have a dramatic effect on participants for all the reasons you point out. Back in the day, there would not be an interface between participants like the internet allows. I bet that keeps them awake at night over there at VERTEX.

I just hope it works and they can iron out any wrinkles.

[jmjm530]

Kalio: if the data on the 12 weekers (which they must have by now) was showing very positive results, we would be hearing about it. Good news travels like wildfire, especially in a case like this with billions riding on it. The ONLY reason to keep the news "close to the vest" is if that the news isn't as good as they hoped it would be. No one keeps GOOD news quiet. The stock price is LOW and getting lower, to me that's not a good sign. I realize the stock price is not a good way to judge, but it is an indicator.
--------------
I disagree. As already discussed, I'm with Mre (hope I'm characterizing your view correctly) that if anything, Vertex would extend the Prove II 12 week group if the news wasn't good with the Prove I 12 weekers. The fact that they aren't doing this can reasonably suggest that the Prove I 12 weekers ARE doing well.

How well? Perhaps not as good as they hope for the 24 week group, but my guess is that will beat SOC's 50-50 mark in only 12 weeks as opposed to 48. Other reasons for not disclosing may be to keep the integrity of the other arms intact and stop people from jumping ship based on a relatively small group at this time.

As to the stock issue, Vertex has tripled in the last year or so. I'm no expert in investing but one major axiom is 'buy on rumor, sell on news'. The "rumor" in this case was the hope that Vertex would be successful. The "news" hopefully is at least some certainty that the trials are working". So, why did the stock decline in the last couple of months. Could simply be profit taking where investors are cashing in on their bet, but still hedging a little until the actual full data comes in. So, I also disagree that today's stock price is "not a good sign".

For better or worse, I think we're all going to have to wait a little longer before we know what is really happening. What we do know is that a couple of our members are still non-detectible after 4 weeks of the 24 week treatment. We've also I believe had one non-responder or drop out. Mre can probably tally the results here better than I, but overall I think they're hopeful, but of course not a large enough sample to draw definitive conclusions from.

-- Jim

[3txsofar]

I think too much is being read into the drop in share price. It was bid up to an all time high of about 45 after the initial release of Prove 1 data in December. This could have been the result of people buying on momentum and shorts being forced to cover as the price spiked.  That high was simply unsustainanble though with approval so far off.  When the company gave no further clinical updates during the quarterly report conference call, the share price dropped further as many were apparently expecting further updates.  You can find the conference call on the company website.  Listen to the Q and A section for an insight on the competence of Wall Street analysts.  

The share price will be volatile until there are more results.  And when there are definitive results, the share price will take off in one direction or the other.  

[mremeet]

I completely disagree that Vertex has the right or "duty" to deprive present and future trial participants from any and all information concerning both efficacy and safety/side effect profile (which goes to efficacy, incidentally). That may be what's most expedient from a corporate perspective, but that's certainly not what's in the best interest of trial participants. Trial participants are human beings by the way, they're not negotiable commodities nor consumable wares. And without trial participants putting their asses on the line, there aren't going to be any future profits.

This is why the FDA is involved with drug trials. They're supposed to police and oversee these trials to make sure drug companies doen't use trial participants in unethical ways (which includes concealing known side effects and reporting likely efficacy). To suggest that it's appropriate to withhold any and all info from trial participants on efficacy and side effects as the data becomes available during the trial, is wrong (other than pre-agreed blinding information). It's also wrong to withhold all information concerning currently known side effects and efficacy from any person considering enrolling in a future trial (Prove 3 and later phase 3 testing, in this case). This information should be provided to trial participants as it becomes available. If you don't understand why this is so, I'd suggest you get down and dirty and learn firsthand what it's like to go through treatment. Experience some of the more severe side effects (especially some of those brought on by an experimental drug with unknown outcomes), grapple with issues of personal safety and possible long term health issues while being "totally" blinded from side effects and efficacy for an ongoing and indefinite period of time?? C'mon, that's absurd and any ethical and well informed person would understand that.

Furthermore, in reference to dointime's situation (and others like him) - if Vertex has data from Prove 1 12 week participants that's currently suggesting no better than 50/50 odds of achieving SVR (or less), then damn right they should increase the duration of dointime's group ("on the fly") and include ribavirin. Do you really think it's appropriate to subject a large group of people who aren't even taking ribavirin to 12 weeks of treatment, when the data they already have from an earlier 12 wk group suggests less than 50% clearance in that group WITH ribavirin? If so, WHY?? Because some rigidly inflexible and unimaginative bean counter at Vertex doesn't want to reformulate his preconceived spreadsheet?? And remember, it's not like all data or information is sacrified or "wasted" by doing this. Far from it! You're merely reformulating that group's treatment criteria to increase their odds of SVR (which will be consistently applied to all within that group) - the data can still be collected, collated and processed into meaningful information, that will still be perfectly useful for the purposes of developing the drug...even moreso, considering it will be more demonstrable of how telaprevir treatment SUCCESS is achieved, as opposed to failure.

Lastly, remember that tinkering with these people's immune systems is very serious business. By exposing these people to very short courses of treatment, you run the distinct risk of breeding drug resistant viral strains within them. This could have a very negative effect on these people's future prospects for treatment success. Relapsing after stopping at 12 weeks could substantially lower the efficacy of the drugs they're currently taking in any future attempt to treat again. Doesn't that count when considering the ethics regarding disclosure to these patients? Doesn't that factor into the importance of Vertex being both able and willing to make "ethical adjustments" to their preconceived trial group formulations on the fly? I absolutely think so - and once again, it does NOT mean that both the trial participants AND Vertex can't get the best of both worlds out of doing so. The two objectives are NOT mutually exclusive.

Also, as an aside, it's looking like they're going to have a placebo group in prove 3 (for relapsers). Not only that, but apparently rescue drugs will be withheld as they were for us during the VX dosing period. Now, how would YOU like to be a relapser and be in that group? And then suffer both anemia and/or neutropenia where your riba and/or IFN dose is cut, especially so early on in the treatment cycle? And remember that the vast majority of trial participants are not sophisticated or savvy to all of the nuances and finer details of treatment like many of us here are. They won't know about or understand the significance of these critically important factors. And it WON'T be fleshed out and explained in their "informed" consent form either. Is that ethical? I don't think so, not one bit.

Oh, and one last thing - the whole concept of all trial participants jumping ship early on if they get wind of the drug's high performance is a fallacy. I've been looking for trial participants since day one (and I'm in the first group Prove 1), and so far there's maybe 15-20 people I've seen online between prove 1 AND prove 2 combined (which constitutes something like 600-700 people). So to characterize the vast majority of all Vertex participants as being (a) online and (b) waiting with baited breath to quit early is absurd; it just ain't happening. And even amongst this tiny group of people that are online, I don't know of a single one of them that has discontinued early yet (other than those that had failed to clear or had unbearable side effects). And the prove 1 folks all know their individual blow by blow viral performance at this point. So we already have the information in hand to suggest to us whether we are likely to get away with quitting early or not right now. And yet no one I know has quit early, even while experiencing GODAWFUL sides (like rash, anemia and even severe degradation of eyesight!). So this concept of non-compliance if the "cat's let out of the bag" is a non-starter. Makes for a nice theory, other than the facts getting in the way.

[dointime]

I'm glad you pointed this out (again) for me about the breakthroughs not being typical.  I didn't really take that in the first time round.

It's so important to see these VL reports and all the different things that can happen, isn't it.  I'm very grateful to everybody who posted their VL results here.

dointime.  

[nygirl7]

I can't believe if the results weren't more positive that this information wouldn't be sneaking out. With the stock dropping and rumors of the therapy not being as effective as originally thought - someone in the company would do some damage control.

I've really always wondered (as I've posted many times) if manipulating the virus into a sort of false "UND" status would have an impact on SVR when the vertex was removed from the equation. That is what has always worried me - we had no data on on any SVR whatsoever and it seemed to me to be the biggest fact we needed to know.

I've always personally thought that since it is a virus very much to me like HIV I would think myself that it will be a real cocktail as well that might be needed.  Different meds for different aspects of the disease and perhaps even a med to take forever to keep the virus supressed since it is not able to be eradicated completely (in many many cases).  Like HIV.  Something to keep the viral load UND so that the liver is able to heal and maintain a  healthy function.

Only time will tell.  But this is one reason I believe anyone with some significant liver damage should not really take a "wait and see" approach. That is ONLY for people with very minimal damage as one never knows how much damage might be INCURRED while you wait.

Remembering that damage does NOT FOLLOW a lateral line of progression - and that it might have taken you 20 years to get to stage 2 but in the next five years you could be cirhotic...it's just a really big gamble.

But thank God for the people that DO the trials so that we do have data.  But it's just not a viable option for everyone.

Peace out!

[Kalio1]

I agree, if the data on the 12 weekers (which they must have by now) was showing very positive results, we would be hearing about it. Good news travels like wildfire, especially in a case like this with billions riding on it. The ONLY reason to keep the news "close to the vest" is if that the news isn't as good as they hoped it would be. No one keeps GOOD news quiet. The stock price is LOW and getting lower, to me that's not a good sign. I realize the stock price is not a good way to judge, but it is an indicator.

Rumors would be flying around everywhere if the news was good.

As I've said all along, without that SVR data, the true value of VX is unknown. People who are told that they should wait because there is this great drug almost ready for use are being sold a bill of goods. Lots of things can knock the virus down, but they can't KEEP IT down after tx ends. Without SVR data showing it really CAN eliminate the virus, people could be waiting only to find in the end they waited for nothing.

[nick m]

10th injection yesterday. 2 to go. I'm in euro group D. Lfts normal between Day 8 and Day 15. Platelets 95 neutrophil 1.27 at Day 43. I'm committed to 12 weeks and off - even if i haven't cleared. Logically, seems little sense in doing 48 weeks of SOC if not UND with the VX in 12 weeks. Although part of me perceives the prudence of another 24 weeks SOC (if i've cleared) as insurance, the reality is i'm not being offered that - so, my decision is 12 weeks and finish - whatever. And that feels good. Incidentally, i was told on my last visit (Day 57) that the ethics and efficacy of treating the 12 weekers who didn't clear had been raised by many researchers in their last check-in on account of the diminishing returns not justifying the impact of treatment on quality of life. I don't know whether i'm imbued with great percipience and uncanny insight or simply awash with naivete and steeped in denial but i am absolutely convinced i'm already clear and i'm going to stay that way. I have the same faith in Boger and Vertex that i reserve for Liverpool FC and Rafael Benitez their manager. I continue to be inspired and supported by the identification warmth and intelligent information i get from you guys. lets hope we're in the last days of this particular virus. Best wishes and good outcomes to all Nick m  

[nygirl7]

Said: Logically, seems little sense in doing 48 weeks of SOC if not UND with the VX in 12 weeks.


No that is not correct.  I was not UND at week 12 but I was by week 24.  My criteria all fell in line with the Berg and Sanchez Tapias studies so I extended treatment until week 72.  Doing this changed my odds greatly.

I don't know if they would let you extend if you have been on Vertex - I guess it hasn't been studied.

And like any of the drugs if it's just not working it's just not working.

[Willy50]

I'm very interested myself but certainly I have no more insight than anyone else.

[Kalio1]

I found this quote below from Dr. McHutchison from Duke.
It could be the higher adverse side effect profile is what is causing the cooling of the stock. With all the worry about side effects from SOC that people go through, the side effect profile of VX as is being reported from McHutchison isn't so great. When considering the "risk ratio" of all this, people should keep in mind that VX will come WITH Interferon, so they have to consider that risk of even more side effects than SOC exists when you factor in the side effects of VX. As to "long term post tx" side effects of VX? No data at all exists to access that risk.
This was dated Feb. of this year.

"Although the latest results are preliminary, they are exciting and confirm findings from initial studies," said Dr. John McHutchison, a Duke University professor who led the new study.

Despite its potency, 9 percent of patients taking VX-950 dropped out of the ongoing trial due to side effects, including rash, gastrointestinal disorders and anemia -- compared with 3 percent taking the standard dual therapy.

Serious adverse events were seen in 3 percent of those taking the Vertex drug, compared with 1 percent taking just interferon and ribavirin.

"The efficacy and safety data were both a little less than expected," Prudential Equity Group analyst Jason Zhang said. But Zhang added that he continues to believe VX-950 has potential to become the new standard of care for the life-threatening liver disease.

While side effects were more pronounced among patients taking VX-950, McHutchison said they should be weighed against the far-worse risks of continued hepatitis C infection. He said the virus causes cirrhosis in about 20 percent of people infected for 20 years or longer. And its damage is the leading reason for liver transplants."

[Willy50]

My response was intended to suggest that there is a reasoning to the news blackout about group results.   I gave a few reasons that they may choose to not share the information to the press.  Although they might temporarily help their stock price in revealing certain information if it hurt validity of the study it would be a false economy.  I'm simply saying don't read too much into the lack of data presented as of late.  I'm not validating, justifying, approving etc.  My understanding was that the participants were being given information as they progressed thru the trials (although THEIRS; not everyones).

You and I are in agreement about making changes "on the fly" if they can do so and you are probably aware that I wrote about it elsewhere about a week ago.  Why not try to salvage a response or SVR; would that not be a fruitful, efficient, humane, and profitable venture?.  The bottom line is that I don't know (what I don't know is a lot,  ; )) whether they have the freedom to deviate from the origional trial plan mid stream.  I have no background in this at all but I admitted my ignorance and proposed the question; wouldn't there be a lot more to learn from making a save in a treatment that was about to fail instead of merely watching it happen and record the data on the failure?

About control groups........I'd guess that they add validity to the trial process.  Adding validity to your trial means that the results presented are less likely to be contested.  A study that is less conclusive is likely to need more follow up tests, have longer or additional trials or greater delays and may ultimately be reviewed longer by the FDA before (and if) it is approved.  I'm sorry if this may seem like it is being distilled into a "the means justify the ends" type argument.  Just as you or I might want to save every trial participant, Vertex may have a longer view; they want to save every percentage point in their trial.  In doing so it may get to market quicker.  As mentioned...... I don't really know who decides, controls and regulates the flow of information on these trials.  If I were a recent non-responder I sure wouldn't want to be in a control arm simply receiving SOC.  On the other hand......if I'd failed monotherapy and was facing liver damage and other extra-hepatic issues I'd still jump at the chance to treat for free. The chance at getting one one of the Telaprevir arms would be icing on the cake.

If they present in Barcelona they should have information on the Prove 1 results and may also share information on the preliminary Prove 2 results.  I'm sorry that there are so many unanswered questions.  I've always been struck by reading your posts about just how much more difficult doing this trial is than I ever imagined.  I hope the results of the trial make this waiting and wondering SO worth it.  

I hope we're still on the "same side".  : )

best,
willy

[willows]

Willy, you did a great job of explaining about the need for NO information to be leaked out.  Even if the stock goes thru the floor, Vertex has to keep all info confidential.  My doctor has to do the same with my info.

The stock is dropping because it was inflated to start with, from wall streets irrational need to seek out the new "pop" stars every month or so.  This month it is ethanol.  So Vertex is "correcting" and the price has ABSOLUTELY nothing to do with whether Telapravir works or not.  

We still have months before we will know all the facts on that front, but Vertex would not continue if the information did not look good.  If it comes to Telapravir not working, the stock will drop like a meteor.  And I will be one sad sad weeping willow.  I don't own any stock, I have High Hopes for a decent tx, but I'll still be sad.

NY girl is right too, and Kalio.  We will watch all the young people right now that are getting infected taking a combo of meds, probably Telapravir and Scherings polymerease inhibitor and maybe no IFN.  In about 10 years.  I have that long left, but hope I have not screwed up my wild wild virus and quasispecies from IFN.

Willow weeping not

[dointime]

Jim wrote:-

"Vertex would extend the Prove II 12 week group if the news wasn't good with the Prove I 12 weekers. The fact that they aren't doing this can reasonably suggest that the Prove I 12 weekers ARE doing well."

It's not over till the fat lady sings.  Changes / extensions would have to go through the ethics committee.  Based on past performance, approval from that quarter would be unlikely to emerge before one minute to midnight.

dointime.    

[poetic_wax]

Vertex has a lot riding on this. Wall St. analysts are idiots.

Maybe the drug isn't going to pan out? Maybe the thing is not the drug we've been waiting for?

Time will tell.

I've seen plenty of stock pumping being done on hep boards by Vertex plants.

[3txsofar]

poetic_wax wrote - "I've seen plenty of stock pumping being done on hep boards by Vertex plants."

I think it is very rare for any company to do something like that. I'm not saying it doesn't happen, but I just believe it is quite rare.

Specifically, I doubt highly that Vertex is involved in any sort of internet chat room pumping.  It is simply not worth the risk, for if they did the harm to Vertex would be incalulable.  And why would they do it anyway? They are not going to benefit from short term swings in the price. The true share price for Vertex will be determined when we have definitive trial data.  Until then, the share price will be quite volatile and I'm sure Vertex knows and understands that.

On the other hand, it is certainly possible for traders who have no connection to Vertex to post in an attempt to inflate or deflate the share price depending on whether they are short or long.  Caveat emptor!

[Forseegood]

thanks for your comments, good observations make very interesting reading...