Key Topic 3: Substantiation

You will need to consider carefully the quality of evidence that is supporting a claim – keep in mind the ‘hierarchy of evidence’. The standard of evidence required to support a particular claim will depend on its nature and the therapy area. In an area that has been well studied, systematic reviews may be easy to find. However in some therapy areas such as very rare conditions the totality of evidence may be from layers lower down in the evidence hierarchy.

Remember to be careful about using exploratory end-points as these will usually be insufficient to support a promotional claim.

Materials based upon ‘real world’ evidence should include a statement making it clear that the information is based on real world evidence and is therefore subject to potential bias. For real world studies the term ‘associated with’ should be used to describe findings as opposed to saying a study ‘showed’ a particular effect e.g. In a real world study, using observational data obtained from patients electronic health records, Product X was associated with a reduced annual rate of exacerbations of COPD compared to Product Y.

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When claims refer to published studies clear references should be given in the material. If using unpublished data to support a claim you should be provided with ‘data on file’ so that you can verify the substantiation of the claim. Refer to the ‘Guidance for Creation of Global Data on File Packets (DoFP))’ for details of how data on file packets are produced and approved, as well as the acceptable format.

Consider these examples:

Substantiation – superiority claims

In the US Cipher Pharmaceuticals sent a promotional email about their product LIPOFEN (fenofibrate). The contents of the email were as follows:

Title: e-pharm alert: All fenofibrates are not created equal

When a patient is prescribed LIPOFEN (fenofibrate capsules USP) a generic fibrate may not be the best option. Only LIPOFEN offers Lidose technology which:

  • Uses a unique lipid melt matrix system not available with any other generic or brand name fibrate
  • Delivers reliable, consistent and uniform delivery
  • Avoids dependence on particle formulation
  • May improve the safety and efficacy of the active ingredient in LIPOFEN by offering more consistent plasma profiles
 

LIPOFEN Takes Particle Size Out of the Equation

  • Other fenofibrates are formulated with small particles, which may affect absorption
  • With LIPOFEN, particle size is not an issue
  • Fenofibrate is in an already-dissolved state, making it readily available for absorption
  • LIPOFEN with Lidose technology offers a very homogeneous distribution of fenofibrate in the mass of excipients
  • No crystals of fenofibrate are observed
 

Assuming that the facts about the formulation of LIPOFEN are true, and that appropriate obligatory information was included, which of the following do you agree with?

  • If factually accurate this email is approvable
  • This email makes superiority claims versus all other fibrates
  • To substantiate these claims I would need to see results of head to head studies against other fibrates
  • If there were no head to head data against other fibrates this email would be misleading
Check answer Ruling
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Ruling

This email was the subject of an FDA warning letter. The FDA stated:

‘In general, claims of superiority must be supported by adequate and well-controlled head-to-head clinical trials comparing appropriate doses and dose regimens of your drug and the comparator drugs. Although we acknowledge that some of the above claims may be true; the totality of the claims and presentations misleadingly implies that Lipofen offers a clinical advantage over other fenofibrate products.’

(There were no head to head comparative data to support the implication of superiority)

 

Product adherence claims

DaraBiosciences Inc made the following claims with respect to their oral formulation of tamoxifen (Soltomox) in the US:

CHALLENGE

  • Compliance and adherence to prescribed tamoxifen therapy is a critical issue in patient care and may affect treatment outcomes.
  • Difficulty swallowing pills may affect both compliance and adherence to prescribed courses of oral solid medications.

SOLUTION

Liquid medication may be preferred vs. pills by many patients

  • Many adults in the USA were reported to have experienced difficulties with swallowing tablets or capsules at some point, even though most had no problems swallowing food or liquid
  • Research shows that women experience more discomfort with pill swallowing compared to men
  • Many adults who have trouble ingesting their medication have not discussed the situation with a health professional

Many adults who have trouble ingesting their medication have not discussed the situation with a health professional.

 
 

Assuming the bullet points are true and can be substantiated, which of the following statements do you agree with?

  • The final claim is supportable because they say it ‘may’ support long term compliance
  • The final claim needs to be supported by some clinical data
  • Without supporting clinical evidence for the final claim it cannot be approved
  • The evidence on compliance issues with tamoxifen tablets would be suitable to support the final claim
Check answer Ruling
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Ruling

These claims were the subject of an FDA warning letter. The FDA stated “Promotional materials are false or misleading if they represent or suggest that a drug is safer or more effective than another drug, when such has not been demonstrated by substantial evidence or substantial clinical experience.

It was considered that the claims suggested that, as a result of its liquid dosage form, Soltamox offers a therapeutic advantage over other available formulations of tamoxifen. There were no studies that specifically evaluated the liquid formulation of tamoxifen with respect to compliance. Therefore the claims could not be substantiated.

 

Overstated efficacy

A complaint was made in Australia about a leavepiece by Pfizer about its product Celebrex (celecoxib) – used to treat the pain of osteoarthritis.

The leave piece included the heading “How can you stop the increasing burden of osteoarthritis?” with graphics of human figures showing the percentages of comorbidities in patients with osteoarthritis. The conditions listed as co-morbidities were depression, sleeping disorders, neuropathic pain and musculoskeletal pain.

The complainant alleged that the cover graphic implied that arthritic burden caused other conditions, depression, sleep disorders, and not that these conditions were merely associated with osteoarthritis.

 
 

Which of the following do you agree with?

  • Such imagery could imply that celebrex has an effect on the co-morbidities listed the Committee deemed this to be the case
  • The complainant is correct that this implies that osteoarthritis causes the co-morbidities the Committee agreed
  • These associated co-morbidities constitute ‘common medical knowledge’ and therefore do not need substantiation
  • The title is specific to osteoarthritis so this claim is substantiated it was deemed that the claim referred to co-morbidities as well as osteoarthritis per se
  • It is obvious that treating osteoarthritic pain would have a positive impact on these comorbidities so the claim can be substantiated the Appeals Committee noted that general practitioners would be aware that chronic pain may impact the presentation of many of the comorbidities, and that it is intuitive that treating the pain associated with osteoarthritis may assist in the treatment of the co-morbidities, but this was not proven.
Check answer Ruling
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Ruling

The Committee agreed that Pfizer had overstated the efficacy of Celebrex and this was upheld on Appeal –Pfizer had to pay a fine of $85,000