IQWiG sees problems in how PROs are included in registrational studies

This week, we are having a brief look at two brief reports on PROs recently published by the IQWiG. We’ll cover:

As usual, there are some recommendations for further reading, if you want to find out more.

Next time, we will focus on how the G-BA selects the appropriate comparative therapy.

IQWiG found that SPCs don’t sufficiently represent PROs

Registrational studies

Registrational or pivotal studies form the basis for the approval of a drug. The EMA assesses these studies at the EU level, or the BfArM at the national level. After regulatory approval, the EMA compiles the product’s accompanying SPC. This SPC should include all relevant study data from these assessments and information on the safe and effective use of the product.

PROs

Last week, I introduced the three overall outcome categories used by the G-BA and IQWiG: mortality, morbidity and HRQoL.

PRO endpoints can include both single and multi-dimension measures of outcomes, such as symptoms and life quality. PROs therefore can cover the two outcome categories morbidity and HRQoL.

Consistent with the regulatory requirements, the G-BA and IQWiG only accept PROs, when they are measured with valid and suitable instruments.

IQWiG review of PRO data in SPCs

PROs are by definition patient-relevant and therefore considered in the early benefit assessments. Their importance for regulators and the inclusion in SPCs though differs from that of HTA bodies.

Therefore, the IQWiG in collaboration with the Drug Commission of the German Medical Association recently conducted a project to review the inclusion of PROs in manufacturer submissions. They evaluated dossiers with RCTs for products launched between January 2014 and July 2018. About 75% of the RCTs included in the dossier contained usable PRO data. However, the authors found that PROs are underrepresented in the SPC. The SPCs mentioned PROs for only 46% of the RCTs with usable data.

For products with RCTs that included suitable PROs, less than half of the SPCs covered the PRO data. Adapted from IQWiG report

This proportion was even lower for oncology drugs, and particularly low in infectious diseases.

In oncology and infectious disease, reporting of PROs in SPCs was particularly low.
Adapted from IQWiG report

This means that important information on the patient perspective is missing from SPCs, despite regulators specifically recommending to include PROs.

IQWiG criticises that the time frames for PRO assessments are often too short in registrational studies

The IQWiG found that registrational studies often evaluate PROs only over a fairly short time, e.g. until the disease progresses.

Regulators might accept this for the drug approval, but when the evaluation time is too short, the G-BA or IQWiG might not consider or can’t interpret the included PRO data. This shorter duration is especially impactful when studies continue after treatment discontinuation, because patients survive for multiple years. For example, if patients reported a worsening of their health status at the end of treatment, it is unclear whether this is maintained, or whether their status improves or further worsens.

However, the longer PRO data would also be important to patients and their clinicians, as this will also inform their decision-making about subsequent treatments.

In the recent example of abemaciclib, this lack of longer-term PRO data was particularly apparent, and negatively impacted IQWiG’s recommendation on the overall additional benefit rating.

Abemaciclib in breast cancer

On 1 March 2022, the IQWiG completed their third assessment of abemaciclib + fulvestrant for the treatment of postmenopausal patients with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer.

The manufacturer provided data from the MONARCH 2 and MONARCH plus studies. The treatment duration in both studies is much longer for the abemaciclib + fulvestrant treatment arm versus the control arm. The observation times for morbidity, HRQoL and AE endpoints are considerably shorter, and only cover the period immediately after treatment. Overall, they only reflect about 1/4 of the overall survival time.

The period of PRO evaluation in the study MONARCH 2 reflects only about 1/4 of the overall survival.
Adapted from IQWiG press release

Thus, the included PROs only allowed an assessment of a very small period of the overall treatment duration. The IQWiG found methodological problems for additional PROs, so could not include them in the assessment.

The IQWiG assessed the treatment effects separately depending on the type of prior treatment.

  1. The subpopulation of women who previously were treated with endocrine therapy was further split into two subgroups: those with and those without visceral metastases.
    • There was a statistically significant improvement in the overall survival for the first subgroup, so the IQWiG recommended a proof of considerable additional benefit.
    • However, the second group did not show an OS gain, and the disadvantages in other endpoints meant overall there was an indication of an additional benefit that is smaller than that of the comparator, fulvestrant monotherapy.
  2. For women who did not previously receive endocrine therapy, the IQWiG concluded that an additional benefit was not proven.

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Anja Pownell

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