Recap

This is part 3 of a multi-part post walking through an appeal of a coverage denial for Adalimumab level testing. This post covers the process of researching a denial to equip oneself with information to use in an appeal.

Getting Lost in the Weeds

It's now time to dig through the pile of legalese and science that has been put on our plate, to determine if the evidence is actually consistent with the insurer's denial rationale. In all likelihood the science, at least, is not¹, but we'll never have a chance to find out if we don't go digging (which could be the intention of the insurer in giving such a broad and vague rationale for denial.)

Denial Rationale

Let's start by summarizing the rationale disclosed in the denial, from the insurer's perspective:

1. Generally, we use MCG guidelines, our own CPBs, your plan benefit documents, and possibly other things to make our coverage decisions.
2. The patient received a service with CPT code 80145, concerned with testing levels of Adalimumab.
3. We specifically used our "CPB: Adalimumab" to determine this denial outcome.
4. One statement we will make is that "Clinical studies have not proven that this service is effective for treatment of the member's condition".

It is important to keep in mind that we cannot read into this rationale in any way, or try to make extrapolations about it's meaning, when we make the appeal. Doing so will only give an insurer more room to maneuver in their response (they'll point out any flawed assumption/interpretation in your appeal, and use it as the sole basis to reject the whole thing). For example, statement 4 does not say that the statement is the sole basis for the denial, and we should not make an argument that relies on that assumption.

Clinical Policy Bulletin

With this summary in mind, let's start by investigating Aetna's CPB on Adalimumab, since Aetna explicitly claims to have used it to make their determination. What specifically in it supports their decision?

Reading through this document, one first notes that Aetna lists the criteria they use to determine whether to grant Initial Approval for use of Adalimumab for various conditions, and what criteria they use to cover continued therapy. These are useful pieces of information, and would be directly relevant if we were, for example, appealing a decision to not approve a pre-authorization request for Adalimumab coverage. In the case at hand, these sections are however not so relevant.

With regard to level testing, the first thing the CPB mentions is in a section titled "Experimental and Investigational". In subsection III of that section, "Serum and Antibodies", it states:

The Anser ADA test and Miraca Life Sciences’ InformTx therapeutic drug monitoring (TDM) measure serum adalimumab (ADA) levels and antibodies to adalimumab (ATA). Aetna considers the Anser ADA test and Miraca Life Sciences’ InformTx therapeutic drug monitoring (TDM) for persons being treated with adalimumab experimental and investigational because the effectiveness of this approach has not been established.

This is just a slightly more specific version of the denial rationale we saw in the letter in the previous post, but this is progress, as we now see two specific tests mentioned. The relevant test in this case is the Anser ADA test.

Let's now see if this CPB has any elaboration of it's claim that the "the effectiveness of this approach has not been established". The only other mention of the drug level test in question in the CPB comes in the "Backgound" section, in the subsection titled "Drug Level Monitoring and Anser ADA".

The statements in this section can be summarized as follows:

• The findings of a particular paper [5] (Chiu et al., 2013) are summarized. According to the CPB, this paper:
  • Studied the efficacy of Adalimumab drug concentration monitoring in patients with Crohn's Disease.
  • Concluded that a positive association between serum adalimumab concentration and remission was identified at several time-points.
  • Stated that further prospective evaluations are needed before recommendations for adalimumab concentration monitoring can be made.
• The findings of another particular paper [6] (Mahil et al., 2013) are summarized. According to the CPB, this paper:
  • Studied the association between serum Adalimumab levels, antidrug antibody levels, and clinical response in patients with psoriasis.
  • Concluded that early adalimumab drug level monitoring at 4 weeks may be useful in predicting treatment response and potentially reduce drug exposure (and associated cost) with earlier review of treatment in those with low levels.
• "Furthermore, the Product Insert of Humira (adalimumab) does not mention Anser ADA and monitoring of drug level."

Let's now debunk the claim (implictly) being made in the denial:

Claim: The three points above collectively show that "Clinical studies have not proven that [Adalimumab level testing] is effective for treatment of [Crohn's Disease]."

Rebutting the claim above is a straightforward process now that we've done the legwork: the three points above have almost no bearing on whether or not clinical studies have proven that Adalimumab level testing is effective for treatment of Crohn's Disease. Here is why:

1. Both studies referenced are from 2013, and it is 2022. Lots of science happens in 9 years. In particular, many studies whose conclusions precisely contradict the claim have been performed since 2013.
2. Both studies referenced conclude that level testing for adalimumab does appear to be useful, in the sense that it correlates with remission and treatment response. While they don't prove the effectiveness of level testing, and they indicate more studies should be done before recommendations are made, their results lend evidence in favor of positive recommendations for level testing (just not sufficient evidence).
3. The second study, (Mahil et al., 2013), studies level testing in patients with psoriasis. There is no apriori or proven reason for why the effectiveness of adalimumab level testing should be the same in treating all conditions, so this study has relatively little (if any) bearing on whether or not Adalamumab level testing is effective for treating Crohn's Disease.
4. The third bullet point is an anecdote, related to a particular product choice of a for-profit corporation trying to maximize it's shareholders' stock values, and has no scientific or medical bearing on the claim at hand, except to the extent that a scientific or medical body requires them to include level testing information on their product inserts. Even if such a requirement were in place, the lack of mention of level testing on the product insert could be due to other factors (e.g. product department made a mistake and forgot to include the info on the insert), and therefore provides no evidence whatsoever for the claim. Frankly, why this is not a valid argument shouldn't need explaining.

Finally, as a last bit of useful information about the CPB to keep in mind when we create our appeal, we note the following line that appears on Aetna's website (see here), detailing the precedence of a member's benefit documents associated with a plan over the CPB, in cases of discrepancy:

If there is a discrepancy between a Clinical Policy Bulletin (CPB) and a member's plan of benefits, the benefits plan will govern.

—Aetna website

With this in mind, let's now review the relevant member benefit contract to see how it can inform the denied claim.

Benefits Contract

Unfortunately, member benefit contracts for particular insurer plans are (AFAIK) generally not made publicly accessible to non-members in any intentional way². Since we need to know details contained in the full plan contract for the purpose of an appeal, I'll outline here the relevant sections of my particular benefit contract.

The key points we need to extract are:

1. How does the plan determine what is covered?
2. Does the plan generally treat coverage for services of the sort being denied?
3. Are there any special exclusions to general coverage practices, in addition to the one listed on the denial, that pertain to the service denied?
4. How does the plan precisely define the terminology used in the denial rationale (e.g. medical necessity, and experimental or investigational services, in this case).

Of relevance here are the following things. My plan states (I'm paraphrasing here at times) that:

• (pg 1, "Let's Get Started" section) Your Plan provides covered benefits. These are Eligible Health Services for which Your plan has the obligation to pay [...] Eligible Health Services are the health care services and Prescription Drugs that:
  • Are listed in the Eligible Health Services Under Your Plan section of the plan.
  • Are not listed in the What your plan doesn't cover - Exclusions and Limitations section.
  • Are not beyond any limits in the schedule of benefits.
• (pg 15, 34, "Eligible Health Services" section) "Physician services" -- services by your physician to treat an illness or injury-- are eligible health services, and in particular you can get those services "from any other inpatient or outpatient facility". "Diagnostic lab work and radiological services" -- diagnostic [...] lab services [...] when You get them from a licensed [...] lab -- are eligible health services.
• (pg 8, "Medical Necessity and Preauthorization Requirements" section) Your plan pays for its share of the expense of eligible health services only if the general requirements are met. They are: - The eligible health service is "Medically Necessary". - You or your provider Preauthorizes the eligible health service when necessary.
• (pg 94, "Glossary" section) To the plan, "Medically Necessary" means: Health care services that we determine a provider exercising prudent clinical judgement, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury, disease, or its symptoms, and that we determine are: - In accordance with generally accepted standards of medical practice. - Clinically appropriate, in terms of type, frequency, extent, site and duration, and considered effective for the patient's illness, injury or disease. - Not primarily for the convenience of the Patient, Physician, or other health care provider. - Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the patient's illness, injury or disease.
• (pg 94, "Glossary" section) "Generally accepted standards of medical practice" means:
  • Standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community.
  • Following the standards set forth in our clinical policies and applying clinical judgement.
• (pg 52, "What Your Plan Doesn't Cover - Exclusions and Limitations" section) We do not cover any healthcare service, procedure, treatment, device or Prescription Drug that is experimental or investigational.
• (pg 52, "What Your Plan Doesn't Cover - Exclusions and Limitations" section) In general, We will not cover any health care service, procedure, treatment, test, device or Prescription Drug that we determine is not Medically Necessary.
• (pg 53, "What Your Plan Doesn't Cover - Exclusions and Limitations" section) We do not cover services that are not listed in this Certificate as being covered.
• (pg 91, "Glossary" section) To the plan, "Experimental" means: A drug, device, procedure or treatment that we find is experimental or investigational because:
  • There is not enough outcome data available from controlled clinical trials published in the peer-reviewed literature to validate its safety and effectiveness for the illness or injury involved.
  • The needed approval by the FDA has not been given for marketing.
  • A national medical or dental society or regulatory agency has stated in writing that it is experimental or investigational or suitable mainly for research purposes.
  • It is the subject of a Phase I, Phase II or experimental or research arm of a Phase III clinical trial. These terms have the meanings given by regulations and other official actions and publications of the FDA and Department of Health and Human Services.
  • Written protocols or a written consent form used by a facility provider state that is experimental or investigational.

With all this source data in hand, we now have a detailed understanding of the only reasons why the service in question could denied be covered according to the plan contract. We'll use this knowledge to help inform our appeal letter in the next post.

Evidence Supporting Medical Necessity

If you've made it this far, I salute you, and don't know how you've done it; this has been an arduous process, and really not much fun at all³. That said, we're almost done with the most grueling part--constructing an appeal argument--and then it will be relatively smooth sailing. The last step in our research process is going to be finding external evidence to support our claim that the denial rationale is faulty, or that our contract guarantees this care should be covered. By external, I just mean things that don't show up in our benefits contracts, or the insurer's guidelines (e.g. the CPB above). Instead this is our chance to look independently at the literature, get testimony from experts (e.g. your physician who ordered the service/treatment), and construct a narrative based in fact about why an overturn of the denial is the appropriate action.

In this case, we've seen that the provided denial rationale hinges on the claim that level testing is ineffective for treatment of "the member's condition" (that's Crohn's Disease here), and that this in turn has so far been backed up by Aetna by reference to only 3 things, all of which we've debunked. While it is useful to have debunked these, it's not enough. Aetna could just respond saying something like "Yes you are correct, those sources indeed do not show level testing is ineffective in this case. However, please see the following 3 resources that do support our claim. We're sorry for the inconvenience, and we'll update our CPB so this is more clear moving forward! Best of luck, appeal denied." As we went over earlier, they can always try to maneuver like this if we leave them room to easily. Instead, we'll supplement our debunking of their use of their references, with a list of our own references to studies showing that in fact, the opposite of their denial rationale is true, and there has been ample work done to show that level testing is effective in treating Crohn's Disease. They can still try to maneuver, but it's going to require more work on their part.

Here's a list of papers I came across, and summaries of their setups and conclusions, that we'll cite in the appeal:

• [1] (Gonczi et al., 2017)
  A population of patients with Crohn's Disease and Ulcerative Colitis were monitored to study the prevalance and frequency of the occurrence of anti-adalimumab antibodies development, and loss of clinical response to adalimumab. The authors concluded that the development of anti-adalimumab antibodies, and the need for dose intensification were frequent during adalimumab therapy and support the selective use of drug level monitoring in IBD patients treated with adalimumab.
• [2] (Papamichael et al., 2019)
  Serum adalimumab concentrations and antibodies to adalimumab were measured among patients with Crohn's Disease split into two cohorts, some of whose adalimumab and adalmimumab antibody levels were proactively monitored to inform treatment, and others who were only monitored reactively (after loss of response). The long term outcome, and liklihood of treatment failure via adalimumab, were compared across these cohorts. Analyses showed that at least one proactive monitoring was independently associated with a reduced risk for treatment failure, and the authors concluded that adalimumab may be associated with a lower risk of treatment failure compared with standard of care in patients.
• [3] (Assa et al., 2019)
  Serum adalimumab concentrations were measured among pediatric patients with Crohn's Disease split into two cohorts, some of whose adalimumab and adalmimumab antibody levels were proactively monitored to inform treatment, and others who were only monitored reactively (after loss of response). The long term outcome, and liklihood of a certain type of remission, were compared across these cohorts. The authors found that proactive monitoring of adalimumab levels, and the proactive adjustment of doses and intervals that facilitates, resulted in significantly higher rates of corticosteroid-free clinical remission than plain reactive monitoring (measuring trough concentration after loss of response).
• [4] (Mitrev et al., 2017)
  This paper aimed to aggregate conclusions of studies on the role of adalimumab level monitoring in IBD patients, to produce the consensus understanding of how useful such monitoring is for optimizing treatment. This is the perfect sort of paper to support our appeal, since it has broad scope, and is supported by significant work from many indpendent sources. 25 experts collectively conducted a literature review, and voted anonymously to produce consensus statements on the topics. Only statements with 80% agreement or more were accepted. The authors concluded that consensus statements deem therapeutic drug monitoring to be effective in optimising anti-TNF agents to treat IBD, especially in situations of treatment failure.

These papers were just random choices from the most well-cited papers on the topic I could find via a google search, and every single one of these papers support our appeal, all of them are more recent than the papers cited by Aetna, and all of them specifically pertain to Crohn's Disease. Collectively they make for a compelling argument that is hard to discount. I don't however doubt that there will be some some rationale provided for discounting this evidence, so that will be fun to waste time with. Stay tuned for that!

References