FDA’s Hollow Medical Device Recall Guidance: Ending Not with A Bang, But A Whimper

By Jeffrey K. Shapiro

FDA has recently finalized the guidance document, now titled “Distinguishing Medical Device Recalls from Medical Device Enhancements.”  We were very critical of the draft guidance, especially the proposal for a new, extra legal reporting requirement for device enhancements (see our previous post here).  

Thankfully, the final guidance does not include this proposal.  The main thrust of it is that one should distinguish a recall from an enhancement by looking at whether the device modification is intended to address a violation of the Federal Food, Drug, and Cosmetic Act against which the agency would take action versus a change that does not address such a violation. 

This concept was present in the draft guidance but is presented more forcefully.  It is a fairly obvious point that did not require a guidance.  On the really difficult questions, the final guidance punts (just like the draft guidance did). 

For example, a “market withdrawal” is by definition a correction or removal involving a minor violation not subject to legal action by the agency.  The determination as to whether a violation is “minor” is, in some cases, not easy.  A device that fails to meet specifications or perform as represented is generally considered adulterated, and action to address such issues would be a recall rather than an enhancement.  However, there are many ways in which performance issues can arise with a device that are not addressed in the specifications or marketing representations.  The final guidance does not discuss these situations.

It is troubling that FDA’s final guidance definition of “device enhancement” still does not explicitly state whether modifications within this definition are to devices already in the field or confined to future production.  The examples do not clarify this point.  The issue of distinguishing a recall from an enhancement (which is the point of this final guidance) should arise only if a firm is correcting or removing devices in the field.  If a firm is modifying future production only, under the regulatory definitions in 21 C.F.R. Parts 7 and 806, there is not a correction or removal, and a Part 806 reporting requirement cannot apply.  (This issue was discussed at length in our post on the draft recall guidance.)

If FDA is impliedly taking the position that modifications of future production only can be a correction subject to Part 806, that is a bold and controversial proposition that the agency should forthrightly state and defend.  On the other hand, if FDA is not taking this position, then this guidance should have said so, if only to correct the misimpression left by the draft guidance.  A guidance is supposed to clarify regulatory requirements, not introduce new uncertainties.

In the end, the final guidance does not have the worst features of the draft guidance, for which industry should be grateful.  At the same time, it does not clarify much or provide much useful guidance, and it will probably soon be forgotten.  And so, a guidance episode that started with a loud bang, ends in a soft whimper.

Does Suboxone Cause SIDS?

Originally posted 1/13/2013

In a recent Google search about Suboxone and pregnancy, one of the top links included the frightening statement that Suboxone and buprenorphine have been linked to SIDS or sudden infant death syndrome, commonly called ‘crib death.’

The statement was from a health forum where a woman wrote about taking Suboxone during pregnancy.  She wrote that her child went through opioid withdrawal after delivery, recovered, and then died two months later from SIDS.  She then claims that her doctors told her that Suboxone was a possible reason for her child’s death.

Suboxone and SIDS?

I don’t know if the woman’s story is true. If it is, I hope my comments do not cause her pain, and I’m sorry for her loss.  But someone should comment on the information, given the number of young women on Suboxone who become pregnant and frantically search the internet for reassurance that their baby will be OK.  I know that pregnant women in my practice lose a great deal of sleep because of guilt over taking buprenorphine.  I am not a SIDS specialist, obstetrician, or pediatrician, and I do not actively follow the SIDS literature.  But I have done some reading to prepare for this post, and I’ll do my best to address the issue.

While the causes of SIDS are not completely understood, a number of factors have been associated with sudden infant death, including maternal age and socioeconomic status (higher rates in infants of poorer, younger mothers), maternal smoking, air pollution, low birth weight, season of birth (higher in infants born in the winter), too high or too low room temperature, male sex, history of premature birth, and bottle feeding (instead of breastfeeding).

One of the biggest risk factors is the easiest to correct: sleeping position. The incidence of SIDS is thought to be about twice as high for babies who are placed prone (face-down).  Since 1992, when 4895 deaths were attributed to SIDS in the US, a public relations campaign to encourage parents to place infants on their backs may have reduced the incidence of SIDS by 50%.  I write ‘may have’ because some experts attribute the decrease to changes in how infant deaths are coded and reported, rather than to a true decrease in cases.

SIDS is a leading cause of death among healthy US infants.  But the actual risk is very low, estimated at about one death from SIDS per 2000 infants.  Deaths from prematurity or from congenital disorders are far more common than SIDS.

When I started this post, I planned to write that the link about buprenorphine causing SIDS was nonsense.  And it may be nonsense.  Realize that it is very difficult to determine the risk factors for things that rarely occur. Only relatively common factors like smoking or prematurity are identified as risks for SIDS in controlled studies.  Unless the connection is very strong (and it isn’t), there are not enough pregnant women on buprenorphine to cause a detectable rise in deaths from SIDS, even in the largest studies.

So what about the link in search engines about SiDS and Suboxone?  From what I can tell, the connection between buprenorphine, Suboxone and SIDS comes from a 2007 study in Finland that prospectively followed 67 women who had babies while prescribed buprenorphine.  In that study, 2 of the 67 infants were reported to have died from SIDS, an incidence of 3%.  A number that high is certainly frightening. But at the same time, an effect that strong would be evident in the larger SIDS studies—- especially those including thousands of women.

A closer look at the Finnish study reveals that the two infants who were thought to have died from SIDS were born to women who were not compliant with the buprenorphine program, i.e. who were using other opioids including heroin.  The associations between SIDS and other risk factors—risk factors that are common among active drug users, such as smoking, low socioeconomic status, low birth weight, and prematurity— confound the results of the study.  Are women struggling with active opioid dependence as likely to know that infants should be placed on their backs? Some SIDS researchers have questioned the numbers from the Finnish study, The forensic uncertainties often associated with SIDS, the significant risk of death associated with co-sleeping, and the challenge of monitoring women who are actively using opioids further confound the Finnish study.

One possible cause of death in SIDS is the accumulation of carbon dioxide in soft blankets or clothing, close to the mouth and nose of a baby sleeping prone (face down).  That cause of death suggests danger for an infant who is for some reason administered opioids, since opioids reduce respiratory response to carbon dioxide.  Opioids are secreted in breast milk, including buprenorphine.  The infants of mothers on Suboxone/Subutex would be tolerant to any buprenorphine in breast milk, since the exposure would be less, if anything, than the exposure during pregnancy.  But mothers who are noncompliant, i.e. intermittently dosing with high-potency opioid agonists, could in theory expose their infants to levels of opioids higher than the infants’ opioid tolerance.  I did not find any reported associations between opioid use, SIDS, and breast feeding.

My take on the data is that the safest situation for any infant is to develop in the womb of a woman who is not drinking alcohol, smoking cigarettes, taking prescription medications, or using illicit opioids.  Out of all of these things, being compliant with a stable dose of buprenorphine or Suboxone likely carries the least amount of risk.  If there was certainty that pregnant women could remain free from opioids after stopping buprenorphine maintenance, then stopping buprenorphine during pregnancy would be a good idea.

But unfortunately, far more women PLAN to remain opioid-free after Suboxone, than actually remain opioid-free.  The intermittent use of illicit opioids, and the malnutrition, cigarette smoking, poor sleep, poverty, needle-sharing, and other risky behaviors that come with opioid dependence create the worst-case-scenario, making the stable use of Suboxone or buprenorphine far safer in comparison to ‘planned abstinence.’

As with everything, there is the world we want, and the world we live in.  I encourage women addicted to opioids to do all in their power to maintain compliance in a Suboxone/buprenorphine program.  I also encourage these women to look forward to a life of doing the ‘next right thing’ for their children— and cutting themselves some slack over taking buprenorphine.  Efforts to stop Suboxone would be better used to avoid alcohol, tobacco, and illicit substances, and to maintain appropriate prenatal care.

In Draft Guidance on Acute Migraine Treatments, FDA Proposes Novel Efficacy Endpoint

By Etan J. Yeshua

Drug developers targeting acute migraines may now have a new path to approval.  In a draft guidance document issued on Tuesday by the Division of Neurology Products ("DNP"), FDA offers a novel primary endpoint that has not been used before to support migraine drug approvals (primarily the triptan class of drugs).  The guidance document also addresses safety considerations, class labeling, and other study design issues.

Migraines are characterized by more than one symptom (i.e., headache, nausea, photophobia, and phonophobia) and approved treatments, at the insistence of DNP, have traditionally demonstrated efficacy on all four of these as co-primary endpoints.  In the past several years, however, DNP has taken the view that a demonstration of efficacy on headache and only one additional co-primary endpoint – nausea – could be sufficient.  Now, DNP has apparently recognized that this paradigm, while lessening the regulatory burden from four endpoints to two, suggests (perhaps inappropriately) that nausea is a more important symptom than photophobia and phonophobia.  DNP has now opened the door to an alternative approach which appears to recognize that not all migraine patients suffer equally from the same secondary symptoms.  As explained in the guidance document, FDA would still require two co-primary endpoints: (1) headache, and (2) an effect on “the [other] most bothersome migraine-associated symptom” as prespecified by each individual subject.  In other words, FDA is considering “having patients prospectively identify their most bothersome migraine-associated symptom in addition to pain,” and efficacy would have to be demonstrated on headache pain and on “the most bothersome associated symptom” – whatever that may be for a given patient.  This new approach could be an effort by FDA to recognize the varied presentations of migraine symptoms as part of the agency’s recent emphasis on “patient-focused drug development.”

The extent to which this alternative approach actually lowers the bar to approval, however, is unclear.  Although DNP is reducing the number of efficacy endpoints necessary for a new migraine therapy to obtain approval, Tuesday’s guidance document leaves out some important details, which counsels toward thorough communication with DNP early in the development process.  For example, the guidance states that, in addition to the two co-primary endpoints, “all . . . migraine-associated symptoms (i.e., nausea, photophobia, and phonophobia) should be assessed as secondary endpoints,” but it does not specify whether and/or to what extent a drug candidate must demonstrate efficacy on one or more of these secondary endpoints.  While pivotal studies are typically not required to demonstrate statistical separation from placebo on secondary endpoints, the history of FDA’s required showing for triptans – efficacy across four endpoints whether they were itemized as co-primary, or primary and key secondary – suggests that the prudent drug developer obtain program-specific clarity on this point from DNP at or before the end of phase 2. 

In addition, the guidance document does not address whether FDA will require studies to enroll some minimum number or proportion of subjects who identify each of the three associated symptoms as the “most bothersome.”  Given that DNP has previously suggested that nausea is the most significant non-headache endpoint, it remains unclear whether a study in which the majority of subjects list, say, phonophobia as their most bothersome symptom, with success on that endpoint but little or no effect on secondary endpoints of nausea or phonophobia, would be sufficient for approval in acute migraine.  Finally, while randomization should assure a balanced distribution of most bothersome symptoms across treatment groups, it is unclear whether DNP would approve a drug that showed a benefit on the co-primary endpoint when, in fact, the results were driven by different identified symptoms in the placebo and treatment groups.

FDA asked that comments about the draft guidance be submitted by December 22, 2014.  Other topics discussed in the document include trial population inclusion criteria, dose selection, concomitant medications, additional secondary endpoints, frequency of data collection, statistical issues, safety considerations, pediatric studies, and labeling.

Choosing Character over Comfort

There are so many times in the day that we get the opportunity to make choices. Do I stay in my warm cozy bed early in the morning or get up to get in a work out? Do I choose the salad and soup or the less healthy hamburger and fries? The list goes on and on. These are examples that while important are certainly not done with serious angst and personal sacrifice. Yet when it comes to relationships and how we deal with conflict or controversy it can be quite stressful. We can choose character building actions that entail facing the issues that are plaguing us or we can choose the comfortable way which would be to ignore or delay a conversation. When I heard this stated as choosing character versus comfort it truly made me stop and think about when I choose comfort over character building.
With our loved ones in addiction it seems we encounter many opportunities to choose character building versus comfort. Early in the journey before I understood about the impact of enabling my daughter I made many decisions to avoid the conflict which made things more comfortable. But when you compound these types of decisions you put yourself in a compromising position to be set up for failure. For example, when my daughter would call me asking for money I had the choice to give it to her and avoid the fight, which was more comfortable, or tell her no and set boundaries. Saying no and setting boundaries is when I began to build character of strength, determination and resolve. Strength because I knew in my heart that she would not use the money for healthy choices, determination because I had to set the precedent that I was not the bank, and resolve because I had to put a stop to the endless struggle of enabling her addiction. In every case that I choose ‘character building’ it not only was the right choice for the moment but also for the long run. When I choose ‘comfort’ it just delayed the inevitable and put off the real work that needed to be done. I am determined to keep focused on character building versus comfort which will help me and those I love.

Smartphone App Boosts Alcoholism Treatment Outcome

Smartphone apps and other mobile technology are emerging as promising tools in medical treatment.

A recent randomized study published in JAMA Psychiatry found evidence that a smartphone app improves alcoholism treatment outcomes.

David Gustafson and colleagues conducted a study funded by the National Institute of Alcohol Abuse and Alcoholism.

A series of 349 adults with DSM-IV alcohol dependence were enrolled as they entered a alcoholism residential treatment program.

Approximately half of the subjects were provided with a smartphone that had an app known as Addiction-Comprehensive Health Enhancement Support System (A-CHESS).

The smartphone with A-CHESS app provided the following support:
  • An audio-guided relaxation program
  • A GPS alert system when users neared a high-risk drinking location (i.e. a bar previously used by the participant)
  • A two-way message system between treatment team and participant
  • A panic button that allowed users to notify two support contacts
  • A log function that allowed the research team to monitor smartphone services used

The key findings from the study included the following for the A-CHESS assigned group:
  • Statistically significant reductions in number of risky drinking days compared to controls (1.39 days per month versus 2.75 days per month)
  • Higher rates of abstinence at 4-, 8- and 12-month follow-up periods
  • Reduction in number of risky drinking days was correlated with number of A-CHESS pages viewed and number of days the service was accessed

The authors noted that some outcome measures were not improved in the A-CHESS group compared to controls including frequency of negative consequences related to drinking.

The cost of the smartphone and A-CHESS app was estimated at $597 per patient during the study.

This study does demonstrated the feasibility and potential utility of using smartphones and treatment augmentation apps for those with alcohol dependence.

The specific components promoting improved outcomes in this study are unable to be identified.

However, the results are encouraging and support further research efforts and evolution of smartphone app design for enhancing the treatment of alcohol dependence and other addictions.

Readers with more interest in this research can access the free full-text manuscript by clicking on the PMID link in the citation below.

Photo of grosbeak is from the author's files.

Follow the author on Twitter WRY999

Gustafson DH, McTavish FM, Chih MY, Atwood AK, Johnson RA, Boyle MG, Levy MS, Driscoll H, Chisholm SM, Dillenburg L, Isham A, & Shah D (2014). A smartphone application to support recovery from alcoholism: a randomized clinical trial. JAMA psychiatry, 71 (5), 566-72 PMID: 24671165

Sublime Recovery vs. Banal Recovery

dialectic3Eve Tushnet offers a really thought provoking discussion of a dialectic involving competing recovery narratives.

First, “sublime” recovery:

In this narrative, addiction and recovery are basically spiritual. Forgive me for drastically oversimplifying a novel I’m loving, but in IJ [Infitite Jest] addiction is often an enslavement of the will or an escape from the self. Recovery is even more insistently spiritual. You recover by giving up and doing as you’re told: Unconditional surrender is the only path to personal peace. If you don’t learn humility through obedience and accept total transformation through surrender to some kind of obscure Higher Power you will destroy yourself and everything you care about.

Then, “banal” recovery:

There’s another narrative, though, which is emerging at sites like The Fix and Substance.com. This is a gradually-coalescing worldview, which typically includes but isn’t limited to “harm reduction” properly understood: ”Harm reduction is a set of practical strategies and ideas aimed at reducing negative consequences associated with drug use. Harm Reduction is also a movement for social justice built on a belief in, and respect for, the rights of people who use drugs. ”

She contrasts the two narratives in several ways, including their view of authority:

The two narratives have differing views of authority: The 12-Steppy model comes across as authoritarian, and can definitely be used as an excuse for cruelty, but it also has an anarchic respect for the wisdom of ordinary people. It attempts to turn followers into leaders through personal guidance. What I’m (again, super-reductively) calling the harm reduction model is simultaneously much more individualistic, and much more reliant on medical expertise. The expert-layperson hierarchy is in many ways more rigid than the sponsor/sponsee relationship. The harm reduction worldview tries to avoid the problems of class- and education-hierarchies by soliciting as much participation as possible from people on the ground, current drug users. “Nothing about us without us” is a slogan of the harm reduction movement, and one with which I agree… but it’s not a slogan AA ever needed, because AA’s whole genesis and development was by “us,” the alcoholics.

She repeatedly acknowledges that she’s oversimplifying the themes in these narratives, but she does a very interesting job contrasting these narratives and the views within them.

An especially interesting point is around “real” recovery.

The increased prominence of the dramatic 12-step narrative, what I’m calling the narrative of sublime recovery, may make it harder for us to accept that anything else is “real” recovery at all.

Maia Szalavitz, a truly invaluable journalist whose work I’ve recommended here before, recently asked, “Most People With Addiction Simply Grow Out of It–Why Is This Widely Denied?” Part of the answer, I think, is that the growing-out-of-it type of recovery is invisible–and it’s invisible because it’s boring.

I have a couple of reactions. First, that I’m not sure I buy the framing of the the “sublime” narrative as being ascendant.

Second, I’d take a step backward on the this matter. Any addict finding a way out of addiction is something to be celebrated, regardless of the path.

The article she references asks why it’s denied that addicts grow of their addiction. I’ve never heard it disputed that lots of problem users moderate or stop without any professional or informal help. I’ve worked in a fairly traditional treatment program that embraces the “sublime” narrative for more than 20 years and taught social work and chemical dependency classes for more than 10 years and we’ve always discussed the fact that the majority of young people who meet alcohol dependence criteria will “mature out”. We’ve emphasized the importance of careful assessment, looking over an extended period of time for factors like multiple failed attempts to stop or moderate, craving/preoccupation, functional impairment, detoxes with returns problematic use, prior treatment episodes, problems with multiple substances, etc., to try to differentiate between problem use and addiction. This can be especially difficult with young people who have never really tried to quit. The point is that DSM Dependence is not a good proxy for addiction. If you use those criteria for identify addicts you’re going to get A LOT of false positives.

The same problem comes up in recovery advocacy, where we hear the frequent references to 23 million recovering Americans. This number is great for advocacy, but it’s based on surveys that count respondents who report once having “a problem” with drug and alcohol and no longer have a problem. Are these people addicts?

The issue isn’t really about denying their recovery, it’s more about questioning their addiction.

It’s also hard for me to imagine that individuals involved would care much. I get the impression that most of them did not think of themselves as addicts and don’t think of themselves as in recovery.

I don’t deny that there are one-wayers who try to invalidate any path but their own. We see that in all cultures/tribes/organizations. And, I think it’s easy to overstate how much tension actually exists. I don’t hear these conversations among recovering people and I don’t hear much tension around it in professional circles. It’s mostly academics, journalists and activists.

However, where there is tension, I wonder how much of the tension around the “realness” of the growing-out-of-it type of recovery is really about the “realness” of the growing-out-of-it type of addiction.

UPDATE: This isn’t to say I believe that addicts can’t experience “natural remission”. As with any illness, it happens. My question is about the number of addicts who grow out of it.

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Traffic Management By Dunkin’ Donuts

There’s a D’n’D just up the street from my wife’s workplace that often causes a traffic backup in the right lane.  I’ve gotten in the habit of staying in the left lane, then changing lanes ahead of the cars turning into the drive-though. This morning I was just getting ready to make my lane change, […]

What Can FDA Do During Drug Inspections: Will FDA Apply Its New Guidance to Other Products?

By Jay W. Cormier & Anne K. Walsh

For managers and employees of drug facilities, the arrival of an FDA inspector can be an anxiety-producing experience.  Adding to the understandable nervousness surrounding an inspection is FDA’s new statutory authority to deem drug products adulterated if a facility delays, denies, limits, or refuses to permit entry during an FDA inspection (previous post here).  On October 21, 2014, FDA issued a Final Guidance that explains what FDA considers to be circumstances that constitute violative delay, denial, limitation, or refusal.  It appears FDA attempted to clarify certain issues from the Draft Guidance, yet, as we will discuss below, the Final Guidance is critically vague and legally questionable in several ways.

Application to Other Products

On its face, the Final Guidance does not apply to inspections of food, medical device, tobacco, and cosmetic facilities, but the Final Guidance is written in sweeping terms (e.g., “This guidance therefore covers facilities subject to inspection under any of the authorities in section 704”, and section 704 governs inspections of “food, drugs, devices, tobacco products, or cosmetics” facilities).  Therefore it is reasonable to expect that FDA will take a similar approach for all FDA-inspected facilities. 

We also note that the Final Guidance specifically includes “outsourcing facilities” that voluntarily register under section 503B of the FDCA, which was added since the Draft Guidance was issued.  FDA encourages such facilities to keep their point-of-contact information with State agencies up to date, as FDA may use State licenses as a source of a facility’s contact information.  The Final Guidance also includes pharmacies that are subject to inspection under section 704(a)(1) “even if [a part of] 704(a)(1) is not applicable because of 704(a)(2).”

(Inappropriate) Regulatory Creep

FDA has frequently issued guidance without going through notice and comment rulemaking.  Try as it may, FDA cannot make law via guidance.   Although the Final Guidance claims it does “not establish legally enforceable responsibilities,” FDA may treat this document as binding authority.  Therefore, the examples that FDA provides throughout the Final Guidance illuminate FDA’s thinking, however erroneous, about the span of FDA’s authority during inspections.  Issues may arise with respect to taking photographs, requiring employees to answer questions, producing documents that are not on-site, or requiring personnel to be present at an inspected facility.

In spite of a lack of statutory language or a binding relevant court opinion, FDA maintains its general rule that investigators are entitled to take photographs during an inspection.  The Final Guidance goes even further than the Draft when claiming that “[i]mpeding or resisting photography” may constitute limiting the investigation and that such a conclusion is in the discretion of the investigator.  FDA’s only example of a “reasonable explanation” for not allowing photos during an inspection borders on ludicrous:  FDA claims it would be reasonable to not allow photos if the light from a camera flash could adversely affect product quality.  As we discussed in depth when the Draft Guidance was issued, the issue of FDA’s authority in the realm of photographs is murky, at best.

The Final Guidance also signals FDA’s view that an inspector has the authority to ask questions of, and demand oral answers from, any individual at a facility –particularly if the individual is designated as a subject matter expert.  Specifically, the Final Guidance states that it would be reasonable for a facility to delay an unannounced inspection if “appropriate personnel are not immediately available to accurately answer the FDA investigator’s questions.”  Given that FDA has no statutory authority to require anyone to answer any questions during an inspection, FDA’s example seems either (1) naïve with respect to the statute, or (2) foundation for a later FDA argument that failure to provide individuals who can “accurately answer the FDA investigator’s questions” is itself a ground for a violation. 

Likewise, the Final Guidance states: “Although FDA recognizes that facilities require a reasonable amount of time to produce records requested, especially if the records are maintained at a different site, a delay in producing records to FDA without reasonable explanation may be considered delaying the inspection.”  This statement shows FDA’s view that it is entitled to records housed at one facility while it is inspecting a different facility.  When inspecting a drug facility, section 704 applies to, among other things, “all things therein (including records, files, papers, processes, controls, and facilities).”  FDCA § 704(a)(1) (emphasis added).  The hypothetical posited in the Final Guidance confirms that FDA’s expectations of facilities extend beyond the already substantial reach Congress delegated to FDA.

It also appears that FDA considers itself entitled to observe a functioning facility during inspection.  The Final Guidance implies that sending staff “home for the day” and telling the investigator that “the facility is not producing any product” would constitute a violative delay.  While FDA may be entitled to observe a functioning facility (provided that the facility is producing product at the time of an inspection), a facility is not required to keep any personnel present at the site beyond the minimal numbers arguably required to carry out the ongoing production runs.  We do not read the Final Guidance as saying that a company cannot send anyone home once it learns of an FDA inspection; nor are we aware of any legal basis for FDA to take such a position.

Reasonable vs. Adequate

In the Final Guidance, FDA made a uniform language shift from use of the word “adequate” to “reasonable,” to define the types of justifications necessary for a delay, denial, limit, or refusal to be excused.  But is there really a difference between the two terms?

The term “adequate” seemed to render FDA the ultimate finder of fact – whether the facility’s reason for a delay is “adequate” to excuse the delay is something that appears to be clearly a discretionary finding provided that such a determination is not arbitrary and capricious.  One may be tempted, therefore, to take refuge in the softer tone of “reasonable,” particularly if that person has spent time in or around a courtroom or law office where the term “reasonable” has a very specific and long-established meaning.  In the legal world “reasonable” is an objective standard – what would a reasonable person do under a given set of facts; could a reasonable jury find the defendant liable or guilty.  Here, FDA should be held to an objective standard that permits discretion only to the extent that its findings are consistent with what a reasonable finder of fact would conclude (a relatively higher standard than an arbitrary and capricious standard). 

The Final Guidance, however, is notably silent regarding what lexicon it employs.  FDA could adopt a legal definition of “reasonable” or it could just as easily decide that it has the sole discretion to determine what constitutes a “reasonable” explanation or justification for a delay, denial, limitation, or refusal.  Because these determinations will be made in practice by investigators in the field rather than attorneys, FDA will likely become its own arbiter of reasonableness.  Under such a scenario, whether there is any daylight between “adequate” and “reasonable” will be an interesting issue to follow.

* * *

The Final Guidance, thus unfortunately, creates issues rather than clarifies issues. Whether FDA will “get away” with the regulatory creep evidenced in the Final Guidance will depend on facilities holding FDA accountable to the four corners of the FDCA and not ceding ground to FDA. 

One thing that is clear, however, is that the Final Guidance is a reminder of the importance of having written internal procedures that specifically address inspectional issues such as whether and who, if anyone, is authorized to speak to FDA during an inspection and the company’s position regarding the taking of photographs and providing documents that are off-site.  When developing and implementing such policies and revising any existing policies to reflect FDA’s new Final Guidance, companies should seek input from counsel.  Once policies are developed, employees should be trained so that all employees understand the company’s positions prior to an FDA inspection.

Peace in the Woodshop

I know why I was able to find peace in my workshop while my son was using.

In my shop I have a Coping Saw.

I know, I know, it's a dumb joke but it works for me.

Suboxone Side Effects Pt. 2

Originally posted 1/2/2013

We can now leave naloxone out of the discussion, and focus on the side effects of Suboxone that are caused by buprenorphine.

Side effects are symptoms caused by a given medication that are not part of the therapeutic benefit of that medication.  Whether a symptom is a side effect depends on the reason for taking the medication.  For example, decreased intestinal motility is the desired effect of opioids used to treat diarrhea, but a bothersome side effect when taking opioids for pain.  The term ‘side effect’ is not on the package insert for medication, the symptoms and actions instead referred to as ‘adverse reactions.’  Package inserts also have a section entitled ‘warnings and precautions’ where the most dangerous adverse reactions are listed.

Some medications have a ‘black box warning’ for adverse reactions that are particularly common or particularly dangerous, consisting of a frightening statement at the start of the package insert (enclosed, naturally, by a black box). Black box warnings in psychiatry include the warning for increased suicidal ideation in children and adolescents treated with antidepressants, and the increased risk of death in people with dementia treated with atypical antipsychotics.

Increased risk of cancer or mutations, and effects on fertility or fetal development, are listed in yet another section entitled ‘nonclinical toxicology.’  They are listed as ‘nonclinical’ because the events do not involve the intended physiologic system or pathway targeted by the medication.  For example, slowing of intestinal activity by opium is either treatment of diarrhea or unwanted constipation, but in either case the outcome is caused by actions of opioids at opioid receptors.  If the opium molecule happened to bind to DNA and cause cancer, the cancer would be nonclinical toxicology, not a side effect.  Carbamazepine decreases the excitability of neurons to prevent seizures, and the sedation caused by the slowing of neurons is considered an adverse reaction. Carbamazepine impairs fetal development through different actions, considered nonclinical toxicology.

All of these divisions can be picked apart so that division of symptoms to one category or another will appear arbitrary.  The system is not precise, by a long shot.  But it may be helpful to be aware that one person’s ‘adverse reactions’ are another person’s intended therapeutic effect.  Some people find the mood stabilizer quetiapine too sedating;  others find the sedation critical to a good night’s sleep.

Allergic reactions are yet another issue.  To put it simply, medication allergies are not something that the medication does to the body, but rather something that the body (the immune response) does to a medication—and the inflammatory fall-out from that reaction.  While the distinction sounds like splitting hairs, the true nature of a reaction can be important.  Nausea is a common adverse event from the action of opioids, used for pain control, at opioid receptors.  Through intellectual laziness, a patient with nausea from morphine in a hospital is often incorrectly labeled as having a morphine allergy. Because of the bureaucracy of modern medicine, the patient has had a very useful medication removed from the armamentarium of treatment options, in essence forever.  Analogous situations are ‘allergies’ to antibiotics like erythromycin.  Allergies tend to become worse with each medication exposure, whereas adverse reactions often go away over time.

Am I going to need a part 3?

Things actually get pretty simple from here. Buprenorphine, like other opioids, has a range of predictable effects that occur along the dosage spectrum— a spectrum that is relative to the person’s opioid tolerance.  Doses of buprenorphine low on the person’s tolerance spectrum fail to have the desired action of preventing withdrawal.  Doses that are close to a person’s tolerance level have the desired therapeutic effect, i.e. blocking withdrawal and a reduction in cravings for opioids.  Doses in this range commonly cause ‘ileus’, i.e. disruption of the normal movement of the intestine.  Ileus in turn causes a number of symptoms, including constipation, cramping, bloating, loss of appetite, and nausea.  Constipation can lead to increased intestinal pressure, leading to hemorrhoids or diverticular disease.

Apart from ileus, buprenorphine and all opioids have direct actions at the base of the brain, at the ‘area postrema’.  Actions at the area postrema cause nausea as an adverse reaction, or in other cases the desired therapeutic effect of induced vomiting.  Nausea is very common when doses of opioids are taken that are at the upper end of tolerance, making nausea particularly common with potent opioids like buprenorphine.  Impaired coordination, slow reflexes, sedation, slurred speech, and somnolence are also caused by strong opioid effects.  Combinations of these effects are obviously quite dangerous.

Opioids reduce the tone of the ‘gastroesophageal sphincter’, increasing the chance of acid reflux, heartburn, hoarseness, and theoretically even esophageal cancer in severe cases.

Cough suppression by opioids might be a therapeutic benefit, but can be an adverse reaction if gastric contents are aspirated into the lungs.

Opioids reduce the response of the brain’s respiratory centers to carbon dioxide, resulting in less drive to breathe.  Carbon dioxide level therefore goes up, and the rise in CO2 increases brain blood volume and in turn, intracranial pressure.  The increased brain pressure reduces the flow of fresh, oxygenated blood into the brain.  Because of this potentially-disastrous sequence of events, opioids must be used with caution in people with head injuries.

Respiratory depression is a common reason for overdose, but even that adverse event can be a desired therapeutic benefit in some cases, for example in patients who are on a ventilator and triggering the machine to cause hyperventilation.  Respiratory depression is even used therapeutically to reduce ‘air hunger’ in people at the end of their lives, to relieve suffering in patients and patients’ family members who are witnessing the death.

I realize that a simple list of side effects would have been easier to read, but like the proverb says about giving a man a fish, I’m hoping that running through the processes will help people figure out, for themselves, what their medications are doing.

What else…  pruritis or ‘itching’ is a common side effect of potent opioids, that doesn’t respond very well to the usual anti-itching treatments like diphenhydramine or steroids.  All common opioids except meperidine (Demerol) constrict pupils, which often makes daytime vision sharper, but impairs night vision by allowing less light to fall on the retina.

Opioids reduce immune function through a number of physiologic interactions, including the presence of opioid receptors on immune tissue. Opioids can have a range of effects on mood and mood disorders.  All opioids, including buprenorphine, have the potential to reduce testosterone levels in men, which in turn can affect mood, libido, and sexual performance.  Opioids alter the release of vasopressin, changing how much water is conserved by our kidneys—which in some people results in more trips to the bathroom at night.

Buprenorphine and other potent opioids interfere with the initiation of ‘micturition’, i.e peeing, particularly in men who are already struggling from an enlarged prostrate.

I know that I’m missing something, and I invite people to write and help me out.  I also realize, as I write this, that I don’t have a package-insert category for a particularly common worry about Suboxone, that it is hurting one’s teeth.  Such a reaction, were it found to be attributable to Suboxone, would probably be considered nonclinical toxicology, although a recent case report proposed that buprenorphine could increase cavities by reducing the immune response in teeth, which sounds more like an adverse reaction.  In either case, I’ve written about the lack of evidence for tooth damage from Suboxone, but the topic still appears on my forum now and then.

That’s all for now…