The Revlimid Paper Chase

No doubt you are used to getting a bit of paper whenever you go to the local pharmacy to pick up a prescription. Nowadays typically there is included with even the most seemingly innocuous of nostrums a "Medication Guide", printed on fan-folded tissue paper, that describes, unreadably and at considerable length, how to take the stuff; how not to take the stuff; all the bad things that could happen, maybe, if you dare to take the stuff; what to do and whom to call if any of these bad things happen; and so on.

But you never, ever read any of this mind-numbing material. Am I right?

News flash: This stuff isn't for you, the patient; it's for every one else involved in the process of delivering the products of the pharmaceutical-industrial complex. It's a liability-limitation mechanism. If something bad happens to you as a result of swallowing a few billion milligrams of Skeezix 100mg tabs, and an ambulance-chaser persuades you to sue the manufacturer, the defense's attorney will want to know whether the plaintiff actually read all this stuff, as required, and fully understood the risks involved. No? Well then: Your honor, this is clearly a deplorable example of the irresponsible misuse of a product the safety of which, when used as directed, has repeatedly been demonstrated blah blah blah.

Every 28 days the UPS man brings a little box to my door. It contains a plastic bottle containing 28 pills, and a quantity of paper. Some of the paper is packing material. But there is also the usual Medication Guide... and 16 standard 8-1/2x11 pages of additional stuff, mostly identical every time, and mostly recycled without much ceremony by yours truly:

An invoice (one page), in the quantity of my minuscule co-pay. The true invoice, for something like $10000, is not included; that is sent to the medical insurance company. I can see it only if I log into my account on the medical insurance web site.

"Important Drug Information" (4 pages). In effect a reprise of the material of the standard Medication Guide, but organized in a different manner, and "personalized" with my name, my oncologist's name, my pharmacy account number, etc.

"Medication Guide" (3 pages). Yet another copy, in a different format, of exactly the same material as the Medication Guide mentioned above.

"General Information about Cancer" (7 pages). Answers such burning questions as "Are there cancer treatment side effects?" (Ummm... Yeah.); and "Do I need to finish my chemotherapy even if I feel better?" (Nah, that's for sissies, pilgrim. But the last page warns against doing anything without asking your doctor first. So we're covered, counselor.)

And finally, a whole page of "Helpful Information Regarding Your Prescription", including such gold as "How do I convert the convertible cap to a non-safety cap for easy opening?".

What a comfort it is, to know this is possible.

Pomalidomide

The multiple myeloma treatment arms race has really been heating up. Practically on the heels of FDA approval of Onyx's carfilzomib (branded as Kyprolis) comes approval for Celgene's latest thalidomide derivative, pomalidomide (branded as Pomalyst). Once again this entry is fenced about by theoretical restrictions (only for patients who have failed at least two other treatments, please) that will yield in practice to further research. Unsurprisingly given its lineage, pomalidomide seems to do better with a low-dose dexamethasone amplifier. Also unsurprisingly, these new agents are doing nothing to reduce the cost of treatment; both will run more or less the same $10000/month as my old reliable Revlimid.

Thalidomide

This Washington Post (actually rehashed AP wire service) article revisits the thalidomide disaster, in the context of the controversy over the original German manufacturer's recent "apology" to the victims, fifty years after the actual events. The article stands on its own merits; but at the very end, it mentions that thalidomide is currently used to treat multiple myeloma, which it identifies as a "bone marrow cancer". Gah.

Carfilzomib

Progress in the treatment of multiple myeloma is slow (let us not speak of "cures" here). Over the past couple of decades, the options developed, aside from the nuclear one (bone marrow or stem cell transplant), are the three FDA-approved agents thalidomide, lenalidomide (Revlimid), and bortezomib (Velcade). These, and various cocktails combining them with each other, with steroids, etc., comprise the universe of weapons commonly used against this cancer.

A few weeks ago, a fourth contestant entered the lists: carfilzomib, called by the brand name Kyprolis by its manufacturer, Onyx Pharmaceuticals, received FDA approval for the treatment of multiple myeloma. As usual, formal approval is for an absurdly narrow scenario, namely for patients who have developed resistance to two of the other therapies and who showed progression within 60 days of completing the last therapy. The clinical trial on which the approval was based involved just 266 such patients. On such slender scientific threads do our fates turn. Of course, the restrictions imposed by the approval are a polite fiction; having received approval for some usage, carfilzomib can now in reality be used by oncologists for any use that seems to them likely to provide some benefit, as indicated by further research. Fortunately.

Back To Aredia

The latest test results show that kappa free light chains are now only very slightly above normal. The kappa/lambda ratio is well within the normal range. So our concerns in this area have eased. But there's always something to worry about. This time, it's glucose, which suddenly spiked up well above the normal range. So I'm supposed to fast for next month's tests. These will also include a thyroid test. I have been noticing my weight drifting downwards again for the past few months. Since there is no evidence of myeloma activity, the possibilities include something going on with the thyroid... or the emergence of a second cancer. We will check the first possibility next month, meanwhile watching for any changes in the weight trend. If it becomes necessary to go on a cancer fishing expedition, the first step would be a CT scan.

Meanwhile, next week I resume Aredia infusions. It has been a year now since I ceased the monthly infusions I was getting. But the oral surgery that prompted this action is now more than seven months past, so it should be safe to resume them. And the spinal MRI carried out in April indicated some weakness around T8 that could be shored up. This time, though, I will be getting infusions only quarterly.

Generic Revlimid?

To completely understand the market and regulatory environments in which Revlimid exists, I would probably have to quit my day job and devote myself to full-time study for an extended period of time. Even then, I'm probably not smart enough to fathom the deepest complexities involved. But let me now take a quick stab at what I think I know about the concept of "generic Revlimid" at this point.

0. Have I mentioned how expensive Revlimid is? It is costing the health insurance company $100+K per year to keep me tuned up with it.

1. Celgene's annual Revlimid revenue is < $2 billion. In the larger scheme of the global pharmaceutical industry this is chump change, but it looms large for Celgene, representing 50-ish% of annual revenue. For the foreseeable future, Celgene really really needs this cash to continue to roll in.

2. Celgene has a protective wall of patents around Revlimid. The earliest of these expires in 2019, but Celgene appears to believe that it has defensible patents that would prevent the production of a "legal" generic version through 2026. That qualifies comfortably as "the foreseeable future".

3. Patents aside, a manufacturer of a generic version of Revlimid (at least one that could be sold legally into the US market) would have to demonstrate "bio-equivalence" of its product with Revlimid. Part of the process of so demonstrating of course involves obtaining samples of the "real thing" for purposes of comparison.

4. A couple of the big Indian generic manufacturers are working on their own versions of lenalidomide (the chemical name of Revlimid). These companies appear to believe that Revlimid's patent wall will be breached in 2019. But they are unable to obtain the requisite samples of Revlimid, because...

5. Distribution of Revlimid is very carefully controlled by Celgene. You can't just stroll down to the corner CVS with a note from your oncologist and score 28 days worth of Revlimid for a mere $10K. You have to be known to Celgene, and convince them on a monthly basis that you continue to be worthy of receiving the magic beans; and you have to work through a specialty pharmacy that has contractual relationships both with Celgene and your health insurance company.

6. ...when the Indian generic manufacturers request samples of Revlimid from Celgene, of course their requests are ever so politely refused. Celgene's position is that it "is under no obligation to supply" potential competitors with samples of its products.

7. Of course the Indian generic manufacturers could obtain Revlimid samples on the street in 10 minutes flat for the right kind of cash. But that would do them no good, because if they were to submit approval applications to the FDA based on bio-equivalence studies in which such samples were used, Celgene would instantly sue the pants off everyone in sight, since obviously these studies could only have been based on "unlawfully obtained" samples -- i.e. samples obtained anywhere other than directly from Celgene itself.

8. So how is it that, here in the land of "free markets", Celgene can get away with controlling the distribution of this product so closely -- so closely that it can't be legally obtained otherwise than directly from the manufacturer? It does so, in fact, in order to comply with FDA regulations.

9. Revlimid, you understand, is a Very Dangerous Drug. It can't be allowed to come anywhere near "a woman who is pregnant, or who could become pregnant", because of a rather extreme risk of severe birth defects. A patient taking it is not allowed to donate blood or sperm. And so on. As such, it is required by the FDA to be covered by a Risk Evaluation and Mitigation Strategy (REMS), under authority conveyed by the FDA Amendments Act of 2007 (FDAAA). And of course the REMS for Revlimid involves very strict control by Celgene over its distribution, lest the stuff fall into the wrong hands, and cause the production of monsters.

10. The FDAAA explicitly forbids using a restricted distribution program to block or delay the development of competing generic products. But of course, in the event of war, it would have to be proven in a court of law that that is what Celgene is in fact doing in this case. And accomplishing that, inclusive of the appeals process, could take years. Maybe until 2026.

More Miscellanea

My apologies for leaving everything hanging for three months, but I've been busy. First, the most recent tests continue to show slightly elevated kappa free light chains, but only slightly. The trend is back towards the normal range. There is no evidence of monoclonal proteins. So the oncologist is pretty relaxed about things right now. He is suggesting that I resume the monthly Aredia infusions (discontinued almost a year ago, in preparation for the extraction of tooth #27), since a set spinal MRIs taken in April indicated some improvements vs. the lytic lesions generally (on one hand), but some additional compression of T8 (on the other). Assuming the medical insurance will work for this, we plan to do this in July.

We did manage to carry out a successful three-week reconnaissance of Indochina in May. Christiana Hospital turned out to have its own travel medicine practice, so there was no need to return to Johns Hopkins. The travel doc, apprised of my situation, made no attempt to dissuade me from making the trip. She provided us with the necessary vaccinations (e.g. Hepatitis A and typhoid fever), as well as with some prophylactic anti-malaria pills (taken starting before the journey and continuing for a week after returning) and antibiotics (Cipro) for "traveller's diarrhea", should it occur. In the event, no one got hurt or ill on the trip, and a good time was had by all.

The biopsies on the tissue samples taken during the recent endoscopy turned up nothing. The GI doc is standing by his diagnosis of mild, "non-specific" (code for "we don't know where this is coming from") gastritis, but otherwise apparently has nothing to offer, at least based on the results of the endoscopy. The Xifaxan he had me try impacted my symptoms not one iota. I may follow up, but based on twenty years of on-again-off-again experience with GI specialists, it wouldn't be with any elevated hopes.