Regular and abbreviated early benefit assessments – Is this the end of orphan drug privileges?

This is the first article in a series about maybe the most important topic influencing market access in Germany: HTAs or early benefit assessments.

While this post focuses on the general process and orphan drug privileges, next week we dive into the details around endpoints.

Technically, the G-BA does not conduct an HTA. Instead, the IQWiG conducts the HTA based on the dossier submitted by the manufacturer. The G-BA then uses this IQWiG assessment plus additional evidence from the manufacturer and other experts in their “early benefit assessment”. I will use the phrase “early benefit assessment” in this article.

Process of an early benefit assessment

  1. When a manufacturer launches their drug in Germany, they have to submit evidence on the efficacy, safety and quality of life in a so-called dossier, to the G-BA. Many sections of this dossier are publicly available.
  2. The G-BA then commissions the IQWiG to evaluate the submitted evidence.
  3. After a maximum of 3 months, the IQWiG shares their recommendation on the additional benefit level. This recommendation is publicly available.
  4. The G-BA will now invite the manufacturer to a meeting, the “oral hearing”. There, the manufacturer can comment on the recommendation from IQWiG and provide additional evidence.
  5. In the next 3 months, the G-BA conducts its early benefit assessment. This is based on the dossier, any additional evidence submitted by the pharmaceutical company, and the IQWiG recommendation. It then publishes its final resolution on the so-called additional benefit (German: Zusatznutzen).

Outcome of an early benefit assessment

If the G-BA identifies an additional benefit, they assign a combination of a level of likelihood and of extent. For example, the G-BA can conclude there is an “Indication of considerable additional benefit”, or “Hint of minor additional benefit”.

If the G-BA found no additional benefit (most often because they did not accept the submitted data), then the G-BA concludes with “No additional benefit (proven)”.

The components of additional benefit assigned in regular early benefit assessments are 1) Level of likelihood (from high to low: proof, indication, hint), and 2) Level of extent (from great to small: major, considerable, minor, non-quantifiable, less/worse), or No additional benefit (proven)
Components of additional benefit assigned in
regular early benefit assessments

This additional benefit rating impacts the price of the medical intervention, but it does not impact reimbursement.

In the future, the G-BA may request that pharmaceutical companies flag whether they plan to launch a product in Germany in the next 6 months. However, the G-BA has not implemented this yet.

Triggers for early benefit assessments

The G-BA will conduct an early benefit assessment for:

  • every pharmaceutical product with a new chemical entity (NCE) that received its marketing authorization on or after 1 January 2011
  • new indications of products that were first approved on or after 1 January 2011.

Since 15 May 2017, pharmaceutical companies can request to merge the HTAs for two or more indications, if they expect to launch these within 6 months of each other.

The G-BA will NOT conduct an early benefit assessment for:

  • new indications of products that were first approved before 1 January 2011
  • new formulations of an existing drug
  • biosimilars, as they are considered to be “generics”, for which no further assessment is needed.
  • reserve antibiotics, i.e., those effective against infections caused by multi-resistant bacterial pathogens, used in strictly defined indications, with only limited alternative therapy options. The additional benefit for these is automatically assumed as proven. In October 2021, the G-BA granted the reserve antibiotics status for the first time – to Fetcroja®. In January 2022, the G-BA added three further drugs, Zavicefta®, Zerbaxa® and Recarbrio®.

Lastly, pharmaceutical companies can also request their products to be exempt from the early benefit assessment if the costs to the SHI funds in the outpatient and hospital sector do not exceed the limit of €1 million within 12 calendar months.

Special status of orphan drugs

Orphan drugs have a special status and undergo an abbreviated early benefit assessment in Germany.

Early benefit assessments for orphan drugs

The steps of the HTA process for orphan drugs are as follows:

  1. When the pharmaceutical company launches their orphan product in Germany, they have to submit an abbreviated dossier to the G-BA. This means that not all sections of the standard dossier are mandatory. The G-BA would still consider the evidence package to be complete.
  2. The G-BA then commissions the IQWiG to only determine the treatment costs as well as the size of the patient population covered by the label of the orphan drug.
  3. After a maximum of 3 months, the IQWiG shares their report on treatment costs and patient numbers.
  4. After another 3 months, the G-BA publishes its final dossier assessment based on the submitted evidence package.

For an orphan drug, the G-BA does not determine whether there is an additional benefit. Instead, an additional benefit is always automatically assumed.

The G-BA can still define the likelihood and extent of additional benefit. However, “Additional benefit not proven” is not an option. If classification into the categories “minor”, “considerable” or “major” is not possible, the G-BA must give a “not quantifiable” additional benefit.

Only when the sales of an orphan product in any 12 months period exceed €50 million or the product loses its orphan drug designation, then the G-BA will conduct a full early benefit assessment to determine the likelihood and extent of additional benefit, after requesting a complete dossier from the pharmaceutical company.

Major additional benefit for orphan drugs

In January 2022, the G-BA assigned a major additional benefit to an orphan drug only for the second time!

It was awarded to blinatumomab for the treatment of Ph-, CD19+ ALL in children aged between 1 and 18 years.

Even though blinatumomab has an orphan drug designation, the manufacturer submitted the results of a randomized, controlled registrational study. The data showed blinatumomab increased the chance of survival and reduced the risk of another relapse compared with intensive chemotherapy. In addition, fewer severe and serious side effects occur under blinatumomab.

Changes to the abbreviated early benefit assessments for orphan drugs

Over the last years, SHI funds have often criticized this special rule applied to orphan drugs. They argue that the assumed additional benefit increases negotiated prices. The new German health minister, Prof. Dr Karl Lauterbach, is supportive of this. In his commentary on the AMNOG report from September 2020, he stated that he’d like to revoke the exemption for orphan drugs. He argues that patients affected by orphan diseases would be put at risk since there is no data and therefore no transparency on the effect of these drugs.

For now, the G-BA sticks to this beneficial management of orphan drugs, but this might change in the near future.

IQWiG report on orphan drugs

In January 2022, the IQWiG published a report concluding that the special status of orphan drugs should no longer be upheld. They request that orphan drugs also should be subject to regular early benefit assessments, including a comparison with an appropriate comparator therapy.

The IQWiG reviewed all 41 abbreviated orphan drug assessments that were later followed by a regular early benefit assessment. These covered 20 different orphan drugs. In more than half of these (54%, 22 assessments), the assumed additional benefit was later not proven in the regular assessment.

Results of the IQWiG review of orphan drugs with abbreviated and regular early benefit assessments shows that 54% of orphan drugs were found to have no additional benefit in a regular early benefit assessment
Results of IQWiG review of orphan drugs with abbreviated and regular early benefit assessments;
modified from IQWiG 2022

Further, the IQWiG noted that it can take a long time before a regular assessment is conducted (if ever). For the reviewed 41 assessments, the average time period between the abbreviated and the regular assessment was 3 years. However, this duration varied between 1 and 9 years across all assessments.

These findings caused the IQWiG to propose an end to the privilege of orphan drugs.

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Anja Pownell

3 thoughts on “Regular and abbreviated early benefit assessments – Is this the end of orphan drug privileges?”

  1. Pingback: Which endpoints are important to the G-BA and IQWiG?
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