Drug shortages in Israel: regulatory perspectives, challenges and solutions

Drug shortages in Israel

Based on the data collected by MoH, between 2013 and 2015, 677 DS notifications were received: 191 in 2013, 240 in 2014 and 246 in 2015. In the US, 117, 44 and 44 DSs were tracked in the years 2012, 2013 and 2014, respectively. The FDA helped to prevent 282 DSs in 2012, 170 shortages in 2013 and 101 shortages in 2014 [3]. Of these DSs, 31% had no available therapeutic alternatives. Sixty to seventy percent of the DSs were communicated by MAH to MoH at the time of DS coming into effect or up to 1 month before, lacking advanced notification essential for management and prevention of DSs. These shortages included sole supplier drugs for various medical conditions, including tranexamic acid tablets and injection, cefotaxim sodium injection, fluphenazine decanoate injection, metolazone tablets, ipatropium bromide respiratory solution, nitroprusside solution, clomifene citrate tablets, oral midazolam, acyclovir ophthalmic ointment, alfacalcidol drops, barium sulfate suspension for radiography, morphine injections, lidocaine injections, midazolam injections, melphalan injections, adrenalin injections, etc.

Figure 1 demonstrates the distribution by ATC (Anatomical therapeutic chemical) categories of DSs in Israel during the years 2013–2015. DSs were disseminated throughout a wide array of the therapeutic groups and affected various aspect of medical care. The most prevalent ones included cardiovascular drugs (15%), anti-infectives for systemic use (16%) and drugs for the treatment of nervous system disorders (21%).

The following case studies provide examples of the complexity of DSs as seen in Israel, some of which may be relevant to other countries as well.

At the beginning of May 2013, the Israeli MoH received a notice of a possible shortage of phenytoin effective almost immediately and anticipated to last for a period of up to 6 months. Phenytoin is an anti-epileptic drug with narrow therapeutic range and non-linear metabolic elimination. Its therapeutic range is so limited, that cases of patients developing breakthrough seizures due to batch-to-batch variations are described in the scientific literature [15]. In dealing with this potential shortage, a careful assessment and risk minimization measures are paramount. In a small country like Israel, where only one drug supplier of phenytoin exists, no local alternatives are available. Attempts by the MAH to find another source of drug supply were futile since the shortage was global. A special task force, including the four Health Management Organizations (HMOs) and leading expert neurologists was established by the Israeli MoH, in order to address this shortage. Due to the narrow therapeutic index of phenytoin, it was important to ensure that the alternative will resemble as much as possible the currently supplied drug to minimize the risk of patients developing breakthrough seizures. In collaboration with the Israeli Neurology Association, a decision was made to supply the remainder of the drug to patients already receiving phenytoin; directing new patients towards alternative therapies. Several potential candidates for phenytoin generics were located in Europe. Since no studies comparing the various phenytoin products were found, it was decided by the task force that comparative bioavailability tests should be carried out to determine which of the available alternatives most resembles the product registered and marketed in Israel. Fortunately, at the last minute, the MAH was able to find an alternative supply site for the original drug and the threat of DS was addressed.

Another example of a DS is Clomiphene citrate, a sole supplier drug used for induction of ovulation. Following intervention by the MoH, the MAH was able to allocate to the Israeli market a supply of the same drug manufactured in Israel for export, thus temporarily resolving the shortage.

Additional imminent shortage of a topical preparation for treatment of burn wounds arose following rapid alert report received by the MoH in 2014 regarding possible cross-contamination with penicillin. Following risk assessment of drug shortage vs. possible side-effect as a result of cross-contamination, it was decided to add a special labeling to the drug’s package notifying the customers that this product should not be used in patients sensitive to beta-lactams. The distribution of the product was accompanied by a Dear Health Care Provider (DHCP) letter and a notice to the public made by MoH.

In March 2014, a routine inspection of the manufacturing facility of oromucosal solution of midazolam, a drug indicated to stop sudden and prolonged convulsive seizures in children, was carried out. The inspection revealed failures in the quality management of the manufacturing process of the drug, raising concerns regarding a potential risk of cross-contamination with amsacrine, another medicine produced at the same site used for the induction and maintenance of remission in acute leukemia in adults. Tests did not find any residuals of amsacrine. As a precautionary step, the drug was recalled in Member States where suitable alternative treatments were available. Due to the lack of available alternatives, the product was classified as critical and it was decided to maintain its supply to the Israeli market.

One of the major concerns in DSs worldwide is disruption in the supply of sterile injectables, resulting in severe impact on public health. During the years 2013–2015 in Israel, 27% of DSs were supply interruptions of injectables and approximately 20% of them were IV injections. Surprisingly, this was in contrast to the situation in the US, where a significantly higher incidence of shortages related to sterile injectable products was noted. For example, according to FDA data in years 2011–2012, sterile injectables accounted for about 70% of all DSs [16].

Throughout 2014–2015, Israel experienced three major DS crises leading to disruption of drug supply; two of them involved local manufacturing sites. In one case, all the production of a MAH was moved to a new manufacturing plant. During the preparation for this major variation, following discussions between the MoH and the MAH, it was decided to increase the inventory of critical drugs to 6 months of use, taking into account the MAH being the sole supplier for these products. Unfortunately, due to unexpected production difficulties at the new facility, these efforts were insufficient, resulting in an immediate shortage of many critically important injectables such as midazolam, lidocaine and morphine. In another incident, one of the major pharmaceutical companies in Israel relocated the secondary packaging site of solid oral dosage form products, creating an ongoing temporary shortage in 90 of the company’s drugs (some of them with a single supplier). Another crisis, related to the transfer of the production of injectables to a new manufacturing facility abroad, is still having an impact on their supply chain, resulting in the need to import non registered alternatives. The MoH is working closely with the MAH, other manufacturers, importers and healthcare institutions to find a solution for this problem.

Etiology of drug shortages in Israel

Steps for managing drug shortages based on the Israeli experience

Unfortunately, without supporting legislation, a regulatory authority cannot instruct a pharmaceutical company/MAH to produce a drug. It also has no capacity to influence a DS that occurs due to commercial agreements between manufacturers and healthcare institutions.

While the root cause of DSs is usually outside the regulator’s control, some of the shortages can be managed and even prevented by activities promoted by the MAH and/or the regulator, especially when both parties collaborate effectively.

One of the key steps in overcoming some of the DSs is ensuring that the regulator receives a notice of the upcoming shortage well in advance. Early disclosure of a shortage by the MAH can allow the regulator to find alternative solutions to overcome the crisis.

In their attempt to prevent and mitigate DSs, the FDA implemented section 506 (c) of the Federal Food Drug and Cosmetic Act requiring MAHs to notify of any manufacturing discontinuance or interruption in manufacturing of the product at least 6 months prior to the date of the discontinuance or as soon as possible and in no case later than 5 business days after DS occurs. EMA requires MAHs to notify the Members State’s competent authority no less than 2 months before the expected interruption in the market.

Until May 2013, the Israeli MoH required MAHs to notify only in cases of permanent marketing termination. The procedure for the notification process in event of drug shortage, also known as Procedure 104, was updated, requiring MAHs to notify the MoH of any permanent or temporary DS anticipated to last more than 2 weeks, at least 6 months prior to the estimated shortage start date. This notification requirement enables the Israeli MoH to monitor DSs in Israel, to receive early notifications of such incidents and to take risk mitigation measures. Additionally the procedure requires the MAH to discuss any future termination with the MoH in order to find acceptable solutions in view of public health considerations. The MoH reserves the right to instruct the MAH to continue distribution of a medicine under special circumstances.

During the years 2013, 2014 and 2015, 58, 71 and 64% (respectively) of the DS notices were received immediately before the shortage (less than 1 month before the shortage came into effect). A decrease in immediate notifications was noted in the months following the update of the procedure. Nevertheless, in spite of the updated requirements, many MAHs still fail to provide the MoH with adequate notice on forthcoming shortages. The lack of compliance with the early notification requirements could be due to the fact that the MAH is not always aware in advance of future shortages and thus is unable to meet the requirement for 6 months notification. This is especially evident when the disruption of the drug supply is caused by global API shortage, quality issues requiring withdrawal from the market of one or more batches of the product, noncompliance with GMP requirements following regulatory inspection and others.

The Israeli MoH developed a protocol for the management of DSs based on country specific experience. According to the protocol, following the MAH notification of the forthcoming shortage of drug with no generic alternatives, the MoH engages all the relevant stakeholders, including Health Care Professionals (HCP), HMOs and/or hospitals and drug importers, to identify a possible solution (e.g. importing similar drug from abroad or issuing instructions to HCPs regarding the shortage and the possible therapeutic alternatives). In some cases, after careful risk evaluation, the MoH may expedite evaluation of drugs that are in shortage to allow the distribution of a drug with relatively minor defects, such as inappropriate labeling or packaging, etc. Cross-contamination of midazolam with the cytotoxic agent amsacrine, described above in this manuscript, is an excellent example of risk management by the Pharmaceutical Division. In another case, similarly to the decision taken by the FDA, a product containing glass particles was allowed to be distributed into the market accompanied by a filter and a DHCP letter instructing the HCP to use the filter to remove potential particles from the product.

According to Procedure 104, it is the responsibility of MoH to notify the public regarding the forthcoming shortage. Furthermore, the MoH actively seeks alternative supply sources of the drug in shortage, to import either a registered or a non-registered drug. Israeli legislation allows for importation of non-registered drugs from authorized countries under article 29 C of the Pharmacist Regulations—Medicinal Products. This allows for a quick and effective way of obtaining drug supply in shortage.

Another step taken by MoH once a shortage is imminent is to instruct the MAH to control more adequately the distribution of the drug in shortage, preventing excess purchase of large quantities by some of the customers and enabling all the stakeholders to receive appropriate restricted drug quantities. An additional strategy may be to instruct physicians, to prescribe the remaining product to defined patient populations and for specific clinical situations, where no appropriate alternatives are available, thus switching or initiating the remaining patients to other therapeutics alternatives.

The presence of a generic drug is not always a guarantee for preventing DSs. The manufacturer may not have the flexibility to increase drug production to meet the national demand in a timely manner, especially at short notice. The MAH of an imported alternative may be unable to increase the supply of the drug into the country due to lack of finished product, previous commitments to other customers and delivery schedules at the manufacturing facility.

In the effort to reduce the number of DSs occurring in Israel each month, the MoH has recently published Procedure 120 which introduces an expedited pathway for authorization of well-established/grandfather drugs. Such drugs were usually registered in Israel in the past or are similar to products registered and marketed for more than 10 years in authorized countries and are imported to Israel under article 29 C. This procedure is currently being evaluated for its impact on reducing the number of non-registered drugs imported to Israel.

One of the causes for cessation of drug distribution in Israel is price reductions. The pricing reference model in Israel is based on overseas reference prices of drugs as well as currency exchange rates. Following the MoH decision on the reference price, HMOs, using an effective tender system may reduce the price even further. This pricing system may be problematic especially with old drugs and small pharma companies. Reference prices for old drugs may be so low that any further decrease makes the production and/or distribution of these important drugs non feasible. Additionally, small local pharma companies may find it difficult to cope with drug suppliers from abroad unwilling to accept the designated price. This challenge has generated important discussions within the Ministry on ways to preserve the availability of such drugs on the market. One of the strategies chosen to overcome this was to suspend any further reductions in drugs prices below 17 new Israeli shekels. The Pharmaceutical Division’s role as an important stakeholder overseeing DSs was an essential factor preventing further reductions below this price.

Finally, as part of Israel preparedness to emergency scenarios (war, earthquake and other natural disasters), it was decided to instruct all MAHs to hold at any time at least 1 month’s supply of all registered drugs in Israel. This strategy was recently published and is monitored and enforced. This requirement is now applicable to both registered drugs and new molecules under evaluation for registration. HMO’s and medical institutions are obliged to ensure a 1 month’s supply of non-registered drugs which are part of the National Health Basket and are imported into Israel under article 29 C of the Pharmacist Regulations—Medicinal Products.