Monday, 9 May 2016

Compassionate Use

Warning! TLAs: CFR; EAP; FDA; IDE; IND; IRB; LOA;
[Three letter acronyms; code of federal regulations; expanded access program; food and drug administration; investigational device exemption; investigational new drug (including biologics); Irish republican brotherhood institutional review board; letter of agreement]
Expanded Access aka Compassionate Use is when the FDA approves the use of a new therapy which has not passed through the ethical and efficacy hoops which they usually require of new drugs (including biologics) and devices. There are good reasons why the FDA exists to ensure that therapeutic drugs (including biologics)  a) work b) are mostly harmless.  If you've ever read the contra-indications on the sheet of small print that comes with all packages of drugs (including biologics) , you'll appreciate that no therapy is without side-effects in at least some of the people who will be taking them.  Here's the list for infliximab:
fever, night sweats, weight loss, tiredness; feeling full after eating only a small amount; pain in your upper stomach that may spread to your shoulder; easy bruising or bleeding, pale skin, feeling light-headed or short of breath, rapid heart rate; or nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); signs of infection (fever, chills, flu symptoms, confusion, or pain, warmth, or redness of your skin); chest pain, ongoing cough, coughing up mucus or blood; shortness of breath with swelling of your ankles or feet, rapid weight gain; numbness or tingling; easy bruising or bleeding, pale skin, unusual weakness; weak feeling in your arms or legs; problems with vision; neck stiffness, seizure (convulsions); pain or burning when you urinate; or red, purple, or scaly skin rash, hair loss, joint or muscle pain, mouth sores; stuffy nose, sinus pain, headache; mild stomach pain; mild skin rash; flushing (warmth, redness, or tingly feeling).
This is not a complete list of side effects and others may occur. Jakers: don't read the small print: I've got 8 of those symptoms already and I can barely spell influxo'mad. It shows the wide impact which the limited repertoire of natural chemical messengers have upon our intricately connected physiological systems.
Catechism:
What is TNF-alpha? It is a key chemical messenger in immunity and inflammation.
What's infliximab? it's a monoclonal antibody [note the *-mab eneding] against TNF-alpha.
What's it good for? Damping down the body's immune response in cases where it is off its trolley.
When is it off its trolley? When an autoimmune disease is abroad: rheumatoid & psoriatic arthritis; Crohn's disease /irritable bowel syndrome / ulcerative colitis; ankylosing spondylitis, Beh├žet's disease and other conditions.
What does it cost? A lot! Somewhere around $2,000 per dose and you typically take it intravenously every couple of months.  So you, or more likely your insurer / government, need to budget $12,000 - $15,000 pa.
What about these side-effects? They're really just covering their ass in the list above.  All those side-effects have been documented in at least one person taking the medication but side-effects are usually rare and influximab works most of the time.  Hence its widespread prescription and the beaming joy of share-holders in distributors Centocor and Shering-Plough. Not all new and expensive drugs have such a small impact w.r.t. side-effects: to make a massive change in the body's immune system has unexpected consequences because your toe bone's connected to your foot bone.  Drugs are delivered intravenously or orally and then course through the system not only affecting the target tissue.

What's with the (including biologics) already? I dunno; but the FDA seems to suffix every use of drug with that phrase.  I suppose that is in case some weasely lawyer makes the claim that biologics are not 'drugs'.  I am only following precedent. What are biologics?  Can we get back to Expanded Access???

An expanded access authorisation will get individual patients access to inadequately tested therapies if they meet certain specific criteria.  Other countries have similar schemes with more, or less, stringent forms to fill in, but the FDA [USA] requires:
  • patients may benefit from the treatment
  • there is no available clinical trial to enrol in
  • it is safe even if outside a clinical trial setting
  • benefit is weighed in the balance against risk
  • no other alternative therapy is available
  • megapharm agrees to give access to the drug
There are very great ethical issues here; because only the desperate customers of Last Chance Saloon qualify for an expanded access program; the desperate are vulnerable and physicians and surgeons are fixers who would often rather do something than do nothing.  If there was anything approaching certainty that the drug will have a positive effect, why then it would have been approved for use already.  Putting a very sick person through an additional slough of suffering with very small chance of successful outcome is not kind. Compassionate Use is, in many cases, an ironic misnomer.

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