J Interven Cardiol 12: 473 - 476, 1999

Introduction of brachytherapy to a German cath lab: How to meet the regulations within a reasonable time frame ?

Sigmund Silber, MD and Armin Schneider, PhD

Dr. Müller Hospital, München, Germany

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Presently, approximately 100 cath labs in the USA and over 20 cath labs in Europe perform intracoronary brachytherapy. In Germany, the first patients were treated with intracoronary afterloading in 1998. In this paper, we describe our experience with the approval processes for clinical research and for routine use with the Novoste BetaCath™ system. First, all major German authorities and laws involved in this process are named and explained. Then, the required steps for obtaining the license for research and routine use are described. Finally, we compare three systems (Beta-Cath™ Novoste, Gamma-IVT™ Cordis and BetaMed™ Boston Scientific) regarding their handling for security and maintenance checks, dosimetry verifications and leakage testing. With the increasing amount of data, obtaining the license for clinical routine use is presently possible in Germany within a reasonable time frame, provided the brachytherapy device has a CE certificate.

 

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Introduction

Intracoronary brachytherapy is increasingly used in cardiac cath labs for prevention and treatment of de-novo lesions, restenotic lesions (without stents) and in-stent restenosis [1-10]. Presently, approximately 100 cath labs in the USA and over 20 cath labs in Europe perform intracoronary brachytherapy with various systems.

In Germany, the first patients were treated with intracoronary afterloading in 1998. In November 1996, we initiated the process for approval to participate in several international multicenter studies. In addition, we received the license for clinical routine use in July 1999.

The purpose of this paper is to describe our experience with the approval process which is inherently different from the regulatory considerations in the USA [11, 12]. Although in Germany the final license is issued by regional (state) authorities, the ways of licensing in other German states can be easily extrapolated from our experience in the state of Bavaria. We assume that this publication will make it easier for others to find the most efficient way to get approval for clinical research and/or clinical routine use.

License for clinical research

Table 1 explains the acronyms used for the authorities and laws mentioned in this context. Table 2 lists the authorities and paragraphs involved in the approval process for clinical research; and Fig. 1 depicts their temporal sequence. Clinical studies can be conducted with devices having or not having the CE mark. Of course, it is easier to get approval for research using a CE-certified device. If the brachytherapy device is not CE-approved or used for purposes other than described in the CE approval, two additional steps must be taken: (1) insurance according to MPG § 17 Pt. 1 Nr. 9 (required by the Ethics Committee) and (2) a special device approval by the LfAS, according to the MPG § 17 Pt. 6 (required for LfU). Then, two independent institutions will review the project: an Ethics Committee and the BfS. The Ethics Committee follows the general rules according to the existing data and possible risks for the patients and critically approves the informed consent form according to the guidelines for GCP (Good Clinical Practice). It is important to emphasize that usually the IRB (Institutional Review Board) approval alone is not sufficient. Not all Ethics Committees are accredited according to MPG §17 Pt. 7 and listed at the BfArM [6]. The BfArM (in Berlin) has to be notified according to § 40 Pt. 1 / 1 / Nr. 6 of the AMG about the clinical trial, with an application for a specific filing number. Working with encapsulated brachytherapy systems (e.g. the Novoste [Novoste Corp., Norcross, GA, USA] or Cordis systems [Cordis Corp., Miami, FL, USA]) makes this step much easier than applying for open radioactive systems (like liquid-filled balloons [13]) which require a pharmacologic-toxicologic examination (risk of inadvertent injection).

Table 1: Glossary of acronyms used for major authorities and laws involved in the process of licensing intracoronary brachytherapy in Germany.

Figure 1: Flow chart for licensing approval for intracoronary brachytherapy to do clinical research. Acronyms are explained in Table 1; for more details, see text.

The BfS is a federal institution, located in Neuherberg / Munich. The experts of the BfS will calculate all radiation questions involved and report directly to the LfU, whether the project including the assumed dosage calculations are reasonable and feasible.

The LfU is the key institution which gives the final approval. The LfU collects all of the above-mentioned reports and requires an additional insurance policy per patient of 1 Mio DM according to the Atomic Law AtDeckV §15 (without a cap). This very high insurance is necessary in hospitals which are not government-run, like all community, city, denominational and private hospitals [14]. Therefore, this insurance is needed by most hospitals in Germany, except the majority of university hospitals. If all papers meet the requirements of the LfU, they will issue a StrlSchV § 3 license, enabling the cath lab to receive the radioactive sources and verify the dose rates.

Before final approval according to StrlSchV §41 [15], the LfAS must come to the cath lab and check the devices for security and maintenance as well as dose rates according to StrlSchV § 76.

License for clinical routine use

The LfU issues the license for clinical routine use according to StrlSchV § 3 and StrlSchV §42 (Table 2). Clinical routine use can only be approved for CE-certified devices. According to the definition of the clinical routine use, approval by the Ethics Committee, BfS or BfArM is not required. Furthermore, the tremendous insurance rate according to the Atomic Law is not necessary. Of course, the performing physicians need additional personal liability insurance policy. After StrlSchV § 3 has been issued by the LfU, the LfAS has to check the devices in the cath lab (StrlSchV § 76) before final approval by the LfU according to StrlSchV § 42.

Table 2: Institutions and paragraphs involved in the licensing process for research and routine use of intracoronary brachytherapy in Germany. For abbreviations, please see Table 1.

It is needless to say that all radiation safety and fire department regulations have to be obeyed either for research or for routine use. In our cath lab, no constructional changes had to be made for using beta radiation with the Novoste™-System. For gamma radiation, safety issues are a concern [8]. Since in Germany no one has so far used gamma radiation in a cath lab, it is not known at the present time whether a lead shield alone is appropriate or if constructional changes will have to be made.

Follow-up requirements

After having received the license for clinical research or routine use, some specific regulatory procedures must be obeyed: security and maintenance checks, dosimetry verifications and leakage testing.

Security and maintenance checks: According to StrlSchV § 76, the integrity of the devices, i.e. their security and maintenance must be checked by the LfAS every time a new transfer device is delivered. As an alternative, th §76 check may be performed at the manufacturer's site by an approved company. If a transfer device is used for several years, this check has to be repeated on an annual basis (Table 3).

Table 3: Requirements to verify device integrity and dosimetry at delivery and during follow-up usage according to German laws and guidelines for quality assurance.

Dosimetry verifications: According to the guidelines for quality assurance, the dosimetry has to be verified every time a new source is delivered. Although some institutions may accept the dosimetry measurements provided by the manufacturers at delivery, most will insist on a local verification. If the source is used for more than 6 months, dosimetry verification becomes a requirement after this time (Table 2).

Leakage tests: According to StrlSchv § 75, leakage tests must be performed annually, preferably after exposure to water with 50 C° for 4 hours. In general, the leakage test is performed by the manufacturer and will be accepted at delivery by most institutions. The next leakage test is due one year after delivery. If the radioactive source is exchanged within one year, no leakage tests are required on-site.

Comparison: To compare the burden of different follow-up tests in the real world of intracoronary afterloaders, we evaluated three different systems (Table 4). Since it is the policy of Novoste to exchange the transfer devices every 6 months, maintenance checks must be performed according to these intervals. Although the half life time of Strontium-90 used in the Beta-Cath™ system is approximately 29 years, Novoste currently recommends exchanging the radioactive sources every year. Therefore, dosimetry verification must be performed 6 months after delivery of the pellets. With this concept for exchanging transfer devices and pellets, leakage tests must not be performed on-site.

With regard to the Gamma-IVT™ system, various factors must be taken into consideration: In contrast to Novoste, Cordis simultaneously exchanges the radioactive sources and the transfer device every four weeks. There-fore, security and maintenance checks must be conducted once a month. The monthly exchange of the transfer devices is related to the short half life time of Iridium-192 of 74 days; and dosimetry verification must be performed every month. On-site leakage tests are not necessary.

The sources of the BetaMed™ system are exchanged every week due to the very short half life time of Yttrium-90 of 64 hours. Therefore, on-site dosimetry verifications must be conducted on a weekly basis. Fortunately, the transfer device (a sturdy afterloader) can stay for a longer period of time, so the security and maintenance checks are necessary only once a year (Table 4).

Table 4: Time intervals for various checks required in Germany with regard to the half-life time of the isotopes and the policy of various manufacturers for exchanging the sources and transfer devices. Security and maintenance checks must be performed every time a transfer device is swapped. Surprisingly, leakage tests do not have to be performed with either system due to the exchange policy of the companies.

Conclusion:

The licensing process for approval to conduct clinical reseach with intracoronary brachytherapy is painful and time-consuming. With the increasing amount of data, obtaining the license for clinical routine use is presently possible within a reasonable time frame, provided the brachytherapy device has a CE certificate.

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References:

 

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Address for correspondence:

Sigmund Silber, MD, FACC
Professor of Medicine
Dr. Müller Hospital
Am Isarkanal 36
D-81379 München
Tel: +49-89-7421510
Fax: +49-89-74215131
e-mail:silber@med.de

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